Alkylsulfonyl-substituted thiazolide compounds

ABSTRACT

A new class of alkylsulfonyl-substituted thiazolide compounds is described. These compounds show strong activity against hepatitis virus.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.12/184,760, filed Aug. 1, 2008, which claims benefit of U.S. ProvisionalApplication No. 60/953,758, filed Aug. 3, 2007, and U.S. ProvisionalApplication No. 61/046,956, filed Apr. 22, 2008, and U.S. ProvisionalApplication No. 61/056,369, filed on May 27, 2008, the entire contentsof each of which are incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The invention disclosed herein was made with Government support underNIAID contract NO1-AI-30046 to Georgetown University Medical Center.Accordingly, the U.S. Government may have certain rights in thisinvention.

BACKGROUND

The present application relates generally to the field of thiazolidecompounds. In particular, the application relates toalkylsulfonyl-substituted thiazolide compounds.

Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are major publichealth problems, causing more than an estimated 500 million chronicinfections worldwide (Chen and Morgan, 2006; Lavanchy, 2004). Bothviruses are a source of significant progressive liver disease, and arethe major risk factors for nearly all cases of primary hepatocellularcarcinoma (Chen and Morgan, 2006; Lavanchy, 2004; Wong and Lok, 2006).Licensed standards of care for both viral infections, while effective inmany cases, are sub-optimal and do not result in virologic or clinical‘cures’ in most individuals (Wong and Lok, 2006). The development ofdrug-resistance in HBV, including strains carrying resistance tomultiple licensed agents is an emerging clinical problem, anddrug-resistance for future HCV therapies is predicted to be asignificant clinical issue (Tomei et al., 2005; Tong et al., Yim et al.,2006).

Thiazolide compounds such as nitazoxanide (NTZ) are anti-infective andpossess activity against anaerobic bacteria, protozoa and viruses (Foxet al., 2005; Pankuch and Appelbaum, 2006; Rossignol et al., 2006a;Rossignol and El-Gohary, 2006). Originally developed as a treatment ofintestinal protozoan infections, the antiviral properties of NTZ werediscovered during the course of its development for treatingcryptosporidiosis in patients with acquired immune deficiency syndrome(AIDS). NTZ is marketed in the United States for treating diarrhea andenteritis caused by Cryptosporidium spp or Giardia lamblia in adults andchildren down to 12 months of age (Alinia®, Romark Laboratories, Tampa,Fla. USA). Clinical trials have demonstrated effectiveness of NTZ intreating diarrhea and enteritis associated with enteric protozoaninfections caused by Cryptosporidium spp, G. lamblia, Entamoebahistolytica and Blastocystis hominis (Amadi et al., 2002; Oritz et al.,2001; Rossignol et al., 2001, 2005, 2006b). Recent randomizeddouble-blind clinical trials have demonstrated effectiveness of NTZ intreating Clostridium difficile colitis in adults, rotavirusgastroenteritis in young children, and rotavirus and norovirusgastroenteritis in adults (Musher et al, 2006; Rossignol et al, 2006a;Rossignol and El Gohary, 2006). The mechanism of action of NTZ againstanaerobic organisms is attributed to interference withpyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electrontransfer reactions, which are essential for anaerobic energy metabolism(Hoffman et al., 2006). Its mechanism of antiviral activity has not beenfully elucidated.

Following oral administration of a 500 mg tablet, NTZ is partiallyabsorbed from the gastrointestinal tract and rapidly hydrolyzed inplasma to form its active circulating metabolite, tizoxanide (TIZ). NTZis not detected in plasma. Maximum serum concentrations of TIZ, reachapproximately 10 μg/mL (37 μM) (Stockis et al., 2002) following oraladministration of one 500 mg NTZ tablet (Alinia®) with food. TIZ isglucurono-conjugated in the liver and excreted in urine and bile.Approximately two-thirds of an oral dose pass through the intestinaltract and is excreted in feces as TIZ (Broekhuysen et al., 2000). Theelimination half-life of TIZ from plasma is approximately 1.5 hours. TIZdoes not inhibit cytochrome P450 enzymes, and therefore, no drug-druginteractions are expected (Broekhuysen et al., 2000; Stockis et al.,2002). The most commonly reported side-effects in clinical trialsinclude mild abdominal pain, headache, diarrhea and nausea, which occurat rates similar to those reported for patients receiving placebo. Whilemost of the clinical experience with NTZ has involved 3 to 14 days oftreatment, continual use of the drug for periods as long as 4 years hasbeen evaluated in patients with AIDS-related cryptosporidiosis withoutany significant drug-related adverse events (Fox et al., 2005;Rossignol, 2006).

Here, results of studies characterizing the activities of NTZ, TIZ andother new thiazolides are presented. In particular, the antiviralactivity of 2-benzamido-5-alkylsulfonyl-thiazoles is demonstrated.

SUMMARY

Disclosed are thiazolide compounds or salts thereof. In someembodiments, the disclosed compounds have a formula (I)

wherein R₁ through R₆ and R₉ are independently chosen from the groupconsisting of H, CN, NO₂, F, Cl, Br, I, —OH, —PO(OR_(a))(OR_(b))₀₋₁,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl, (C₃-C₈)-cycloalkyl-(C₂-C₄)-alkenyl,(C₃-C₈)-cycloalkyl-(C₂-C₄)-alkynyl, (C₅-C₈)-cycloalkenyl,(C₅-C₈)-cycloalkenyl-(C₁-C₄)-alkyl,(C₅-C₈)-cycloalkenyl-(C₂-C₄)-alkenyl,(C₅-C₈)-cycloalkenyl-(C₂-C₄)-alkynyl, (C₁-C₆)-alkoxy,(C₂-C₆)-alkenyloxy, (C₂-C₆)-alkynyloxy, (C₂-C₆)-alkoxy-(C₁-C₄)-alkyl,(C₁-C₆)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkoxy-(C₂-C₄)-alkenyl,(C₁-C₆)-alkoxy-(C₂-C₄)-alkynyl, (C₂-C₆)-alkenyloxy,(C₂-C₆)-alkenyloxy-(C₁-C₄)-alkyl, (C₂-C₆)-alkenyloxy-(C₂-C₄)-alkenyl,(C₂-C₆)-alkenyloxy-(C₂-C₄)-alkynyl, (C₂-C₆)-alkynyloxy,(C₂-C₆)-alkynyloxy-(C₁-C₄)-alkyl, (C₂-C₆)-alkenyloxy-(C₂-C₄)-alkenyl,(C₂-C₆)-alkenyloxy-(C₂-C₄)-alkynyl, (C₃-C₈)-cycloalkoxy,(C₃-C₈)-cycloalkyl-(C₁-C₄)-alkoxy,(C₃-C₈)-cycloalkyl-(C₂-C₄)-alkenyloxy,(C₃-C₈)-cycloalkyl-(C₂-C₄)-alkynyloxy, (C₅-C₈)-cycloalkenyloxy,(C₅-C₈)-cycloalkenyl-(C₁-C₄)-alkoxy,(C₅-C₈)-cycloalkenyl-(C₂-C₄)-alkenyloxy,(C₅-C₈)-cycloalkenyl-(C₂-C₄)-alkynyloxy,(C₂-C₆)-alkoxy-(C₂-C₆)-alkylamino, (C₁-C₆)-hydroxyalkyl, (C₁-C₆)-acyl,(C₁-C₆)-acyloxy, aroyloxy, arylalkanoyloxy, arylalkenoyloxy,heteroaroyloxy, heteroarylalkanoyloxy, heteroarylalkenoyloxy,(C₁-C₆)-alkylamino, (C₂-C₆)-dialkylamino, (C₂-C₆)-alkylaminoalkyl,amido, (C₁-C₆)-alkylamido, (C₁-C₆)-dialkylamido, (C₁-C₆)-haloalkyl,(C₁-C₆)-perhaloalkyl, (C₁-C₆)-perhaloalkoxy, SR_(e), (C₁-C₆)-alkylthio,(C₁-C₆)-alkylthioalkyl, (C₁-C₆)-alkylsulfonyl,(C₁-C₆)-alkylsulfonyl-(C₁-C₆)-alkyl, (C₂-C₆)-alkenylsulfonyl,(C₂-C₆)-alkynylsulfonyl, (C₁-C₆)-hydroxyalkylsulfonyl,—SO₂—(CR₇R₈)₀₋₄—COOR_(b), (C₃-C₈)-cycloalkylsulfonyl,(C₃-C₈)-cycloalkyl-(C₁-C₄)-alkylsulfonyl,(C₃-C₈)-cycloalkyl-(C₂-C₄)-alkenylsulfonyl,(C₃-C₈)-cycloalkyl-(C₂-C₄)-alkynylsulfonyl,(C₅-C₈)-cycloalkenylsulfonyl,(C₅-C₈)-cycloalkenyl-(C₂-C₄)-alkylsulfonyl,(C₅-C₈)-cycloalkenyl-(C₂-C₄)-alkenylsulfonyl,(C₅-C₈)-cycloalkenyl-(C₂-C₄)-alkynylsulfonyl,(C₂-C₆)-alkenylsulfonyl-(C₁-C₆)-alkyl,(C₂-C₆)-alkynylsulfonyl-(C₁-C₆)-alkyl,(C₁-C₆)-hydroxyalkylsulfonyl-(C₁-C₆)-alkyl,(C₃-C₈)-cycloalkylsulfonyl-(C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl-(C₁-C₄)-alkylsulfonyl-(C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl-(C₂-C₄)-alkenylsulfonyl-(C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl-(C₂-C₄)-alkynylsulfonyl-(C₁-C₆)-alkyl,(C₅-C₈)-cycloalkenylsulfonyl-(C₁-C₆)-alkyl,(C₅-C₈)-cycloalkenyl-(C₁-C₄)-alkylsulfonyl-(C₁-C₆)-alkyl,(C₅-C₈)-cycloalkenyl-(C₂-C₄)-alkenylsulfonyl-(C₁-C₆)-alkyl,(C₅-C₈)-cycloalkenyl-(C₂-C₄)-alkynylsulfonyl-(C₁-C₆)-alkyl,arylsulfonyl, arylalkylsulfonyl, arylalkenylsulfonyl,heteroarylsulfonyl, heteroarylalkylsulfonyl, heteroarylalkenylsulfonyl,(C₁-C₆)-alkylsulfonamido, N,N′—(C₁-C₆)-dialkylsulfonamido,(C₁-C₆)-sulfonamidoalkyl, sulfonamidoaryl, sulfonamidoarylalkyl,sulfonamidoarylalkenyl, sulfonamidoarylalkynyl, aryl (such as phenyl),arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino,arylalkylamino, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl,heteroarylalkenyl, heteroarylalkynyl, heteroarylalkoxy,heteroarylalkylamino, heteroarylalkylthio, heteroaryloxy,heteroarylalkoxy, heteroarylthio, heteroarylalkylthio, heteroarylamino,heteroarylalkylamino, lower cycloalkyl, lower cycloalkylalkyl (see aboveexpanded scope), heterocyclo-(C₁-C₄)-alkyl, heterocyclo-(C₂-C₄)-alkenyl,(C₄-C₈)-heterocyclo-(C₂-C₄)-alkynyl, (C₄-C₈)-heterocyclo-(C₁-C₄)-alkoxy,(C₄-C₈)-heterocyclo-C₂-C₄)-alkenyloxy,(C₄-C₈)-heterocyclo-(C₂-C₄)-alkynyloxy, —(CR₇R₈)₀₋₄—OR_(a),—(CR₇R₈)₀₋₄—COOR_(b), (CR₇R₈)₀₋₄—CONR_(a)R_(b), —NH—(CR₇R₈)₀₋₄—CO—R_(c),—(CR₇R₈)₀₋₄O—CO—R_(d), and —(CR₇R₈)₀₋₄-L₂-SO₂-L₁-R_(x), any of which maybe optionally substituted;

provided at least one of R₁-R₆ or R₉ must be an—(CR₇R₈)₀₋₄-L₂-SO₂-L₁-R_(x);

wherein R₇ and R₈ are independently selected from the group consistingof hydrogen, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, (C₁-C₆)-hydroxyalkyl,aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl,heteroarylalkenyl, lower cycloalkyl, lower cycloalkylalkyl, andheterocycloalkyl, any of which may be optionally substituted;

or R₇ and R₈, together with the atoms to which they are attached, may bejoined to form an optionally substituted 4- to 8-memberedheterocycloalkyl or an optionally substituted 3- to 8-memberedcycloalkyl ring, any of which may be optionally substituted;

wherein R_(a) through R_(e), each independently of one another, ischosen from H, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl, (C₄-C₈)-heterocyclo alkyl, (C₄-C₈)-heterocycloalkyl-(C₁-C₄)-alkyl, aryl, arylalkyl,(CH₂)₀₋₂-phenyl, heteroaryl, heteroarylalkyl, (C₁-C₆)-alkoxy,(C₂-C₆)-alkenyloxy, (C₂-C₆)-alkynyloxy, (C₃-C₈)-cycloalkoxy,(C₃-C₈)-cycloalkyl-(C₁-C₄)-alkoxy, (C₄-C₈)-heterocycloalkoxy,(C₄-C₈)-heterocycloalkyl-(C₁-C₄)-alkoxy, aryloxy, arylalkoxy,heteroaryloxy, heteroarylalkoxy, (C₁-C₆)-alkylamino,(C₂-C₆)-dialkylamino, (C₂-C₆)-alkylaminoalkyl, (C₃-C₈)-cycloalkylamino,(C₃-C₈)-cycloalkyl-(C₁-C₄)-alkylamino, (C₄-C₈)-heterocycloalkylamino,(C₄-C₈)-heterocycloalkyl-(C₁-C₄)-alkylamino, arylamino, arylalkylamino,heteroarylamino, heteroarylalkylamino, and (C₂-C₆)-alkenylamino, any ofwhich may be optionally substituted;

wherein L₁ and L₂ are independently selected from the consisting of abond, O, —N(R_(y))—, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl,heteroarylalkenyl, heteroarylalkynyl, each of which may be optionallysubstituted with 1 to 3 substituents, provided that L₁ and L₂ are notsimultaneously O;

wherein R_(x) and R_(y) are independently selected from the groupconsisting of H, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl,(C₄-C₈)-heterocycloalkyl, and (C₄-C₈)-heterocycloalkyl-(C₁-C₄)-alkyl,aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl,heteroarylalkenyl, heteroarylalkynyl, each of which may be optionallysubstituted with 1 to 3 substituents;

wherein any of the preceding carbon-containing Rx and Ry may have fromzero to nine H atoms replaced by F, Cl, Br, and/or I.

In some embodiments, R₁, R₂, R₃, R₄, or R₅ is one or more —OS(O₂)Rx,wherein Rx is defined as above. In some embodiments, R₁, R₂, R₃, R₄, orR₅ is one or more —OSO₂—CH₃.

In some embodiments, R₆ and R₉ are H or —SO₂-alkyl, preferably —SO₂CH₃.

In one embodiment, the compound has the following formula:

Also disclosed are pharmaceutical compositions comprising the compoundsand a carrier (e.g., a diluent or excipient). The pharmaceuticalcomposition may comprise an effective amount of the compound fortreating HCV infection.

Also disclosed are methods for treating HCV infection comprisingadministering the disclosed pharmaceutical compositions to a patient inneed thereof. For example, the patient may have a chronic HCV infection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides the structures of exemplary thiazolides as disclosedherein.

FIG. 2 provides examples of the analysis of interactions betweeninterferons in combination treatments. Analysis of combination therapieswas performed using Calcusyn™ software (Biosoft, Inc., Cambridge, UK).Panels A and B display anti-HBV treatments; panels C to F displayanti-HCV treatments. Two types of evaluations are presented. Panels A,C, and E present CI-Fa (Combination Index-Fraction (of virus) affected)plots (Belen'kii and Schinazi, 1994). For these plots, a combinationindex [CI] greater than 1.0 indicates antagonism and a CI less than 1.0indicates synergism. Evaluations of synergy, additivity (summation), orantagonism at different levels of virus inhibition (e.g. 5% (Fa=0.5) to99% (Fa=0.99)) are provided by the plotted lines and points. Dottedlines in panel A indicate 1.96 standard deviations (not shown in panel Cfor clarity). Panels B, D, and F present conservative isobolograms. Forthese plots, EC₅₀, EC₇₅, and EC₉₀ (50%, 75%, and 90% effective antiviralconcentrations) values for the combination treatments are displayed assingle points. Three lines radiating out from the axes denote theexpected (e.g. additive) EC₅₀, EC₇₅, and EC₉₀ values for drugcombinations as calculated from the monotherapies. EC₅₀, EC₇₅, and EC₉₀values for the combinations that plot to the left (e.g. less than) ofthe corresponding lines indicate synergy, and values plotting to theright (e.g. greater than) of the corresponding lines indicateantagonism.

FIG. 3 illustrates the effect of NTZ on HBV nucleic acid and proteinlevels in 2.2.15 cells. Cultures of 2.2.15 cells were treated understandard procedures (Korba and Gerin, 1992, Antiviral Res. 19:55). HBVnucleic acids levels were determined by quantitative blot hybridizationanalysis (Korba and Gerin, 1992, Antiviral Res. 19:55; 1995, 28:225).HBV proteins levels were determined by semi-quantitative EIA (Korba andGerin, 1992, Antiviral Res. 19:55; 1995, 28:225). Samples were diluted(2 to 10-fold) to bring levels into the dynamic response ranges of theEIA's. HBV virion DNA, HBsAg, and HBeAg were analyzed from culturemedium samples. HBV RNA, HBV RI (HBV DNA replication intermediates), andHBcAg were analyzed from intracellular lysates.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Unless otherwise specified, “a” or “an” means “one or more.”

Disclosed are thiazolide compounds having a formula (I)

wherein R₁-R₆ have the meanings set forth above. In some embodiments,R₁, R₂, R₃, R₄, or R₅ is a —OS(O₂)Rx, wherein Rx is alkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, each of which may be optionallysubstituted. In some embodiments, R₁, R₂, R₃, R₄, or R₅ is —OSO₂—CH₃.

In some embodiments, one of R₆ or R₉ is H and the other is —SO₂-alkyl,preferably a —SO₂CH₃, —SO₂Et, —SO₂iPr, —CH₂SO₂Me, —NHSO₂Me or—SO₂-cyclopropyl.

The disclosed compounds include2-benzamido-5-methylsulfonyl-thiazolides,2-benzamido-4-methylsulfonyl-thiazolides and2-(thiazol-2-ylcarbamoyl)phenyl methanesulfonates.

In some embodiments of the compounds of formula (I), R₁ is chosen fromH, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, phenyl, F, Cl, Br,I, (CH₂)₀₋₂—OR_(a), a NO₂, (CH₂)₀₋₂—COOR_(b), NH—(CH₂)₀₋₂—CO—R_(c),(CH₂)₀₋₂O—CO—R_(d), SR_(e), PO(OH)(OH)₀₋₁, and a SO₂CH₃; R₂ through R₅are, each independently of one another, chosen from H, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, phenyl, F, Cl, Br, I, (CH₂)₀₋₂—OR_(a),a NO₂, (CH₂)₀₋₂—COOR_(b), NH—(CH₂)₀₋₂—CO—R_(c), (CH₂)₀₋₂O—CO—R_(d);SR_(e) and PO(OH)(OH)₀₋₁; wherein R_(a) through R_(e), eachindependently of one another, is chosen from H, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, and (CH₂)₀₋₂-phenyl; wherein R₆ is Hor a SO₂CH₃; wherein the alkyl, the alkenyl, and the alkynyl in eachcase have from zero to nine H atoms replaced by F, Cl, Br, and/or I; andwherein if R₁ is a SO₂CH₃, then R₆ is H; and if R₆ is a SO₂CH₃, then R₁is not SO₂CH₃.

In further embodiments of the compounds of formula (I), the compoundshave formula (I), in which: R₁ through R₅ are, each independently of oneanother, chosen from H, (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl,phenyl, F, Cl, Br, I, (CH₂)₀₋₂—OR_(a), NO₂, (CH₂)₀₋₂—COOR_(b),NH—(CH₂)₀₋₂—CO—R_(c), (CH₂)₀₋₂O—CO—R_(d); SR_(e) and PO(OH)(OH)₀₋₁;wherein R_(a) through R_(e), each independently of one another, ischosen from H, (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl, and(CH₂)₀₋₂-phenyl; wherein the alkyl, the alkenyl, and the alkynyl in eachcase have from zero to nine H atoms replaced by F, Cl, Br, and/or I; andR₆ is a SO₂CH₃.

In further embodiments of the compounds of formula (I), the compoundshave formula (I), in which: R₁ through R₅ are, each independently of oneanother, chosen from H, (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl,phenyl, F, Cl, Br, I, (CH₂)₀₋₂—OR_(a), a NO₂, COOR_(b), NH—CO—R_(c),O—CO—R_(d); SR_(e) and PO(OH)(OH)₀₋₁; wherein R_(a) through R_(e), eachindependently of one another, is chosen from H, (C₁-C₄)-alkyl,(C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl, and (CH₂)₀₋₂-phenyl; wherein thealkyl, the alkenyl, and the alkynyl in each case have from zero to nineH atoms replaced by F, Cl, Br, and/or I; and R₆ is SO₂CH₃.

In further embodiments of the compounds of formula (I), the compoundshave formula (I), in which: R₁ through R₅ are, each independently of oneanother, chosen from H, (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl,phenyl, F, Cl, Br, I, OR_(a), a NO₂, COOR_(b), NH—CO—R_(c), O—CO—R_(d);SR_(e) and PO(OH)(OH)₀₋₁; wherein R_(a) through R_(e), eachindependently of one another, is chosen from (C₁-C₄)-alkyl,(C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl, and (CH₂)₀₋₂-phenyl; wherein thealkyl, the alkenyl, and the alkynyl in each case have from zero to nineH atoms replaced by F, Cl, Br, and/or I; and R₆ is SO₂CH₃.

In further embodiments of the compounds of formula (I), the compoundshave formula (I), in which: R₁ through R₅ are, each independently of oneanother, chosen from H, (C₁-C₄)-alkyl, F, Cl, Br, I, a NO₂, andPO(OH)(OH)₀₋₁; wherein R_(a) through R_(e), each independently of oneanother, is chosen from H and (C₁-C₄)-alkyl; and wherein the alkyl, thealkenyl, and the alkynyl in each case have from zero to nine H atomsreplaced by F, Cl, Br, and/or I. In further embodiments, the compoundshave formula (I), in which: R₁ through R₅ are, each independently of oneanother, chosen from H, (C₁-C₄)-alkyl, F, Cl, Br, I, a NO₂, andPO(OH)(OH)₀₋₁; wherein R_(a) through R_(e), each independently of oneanother, is chosen from H and (C₁-C₄)-alkyl; and R₆ is a SO₂CH₃.

In further embodiments of the compounds of formula (I), the compoundshave formula (I), in which: R₁ through R₅ are, each independently of oneanother, chosen from H, F, Cl, Br, I, a NO₂, and PO(OH)(OH)₀₋₁; and R₆is a SO₂CH₃.

In further embodiments of the compounds of formula (I), the compoundshave formula (I), in which R₁ through R₅ are, each independently of oneanother, chosen from H, (C₁-C₆)-alkyl, F, Cl, Br, I, (CH₂)₀₋₂—OR_(a),NO₂, COOR_(b), NH—CO—R_(c), O—CO—R_(d); SR_(e) and PO(OH)(OH)₀₋₁;wherein R_(a) through R_(e), each independently of one another, arechosen from H and (C₁-C₆)-alkyl; and R₆ is SO₂CH₃.

In further embodiments of the compounds of formula (I), the compoundshave formula (I), in which: R₁ is a —OS(O₂)Rx, wherein Rx is alkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, each of which may beoptionally substituted; R₂ through R₆ are, each independently of oneanother, chosen from H, (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl,phenyl, F, Cl, Br, I, (CH₂)₀₋₂—OR_(a), NO₂, (CH₂)₀₋₂—COOR_(b),NH—(CH₂)₀₋₂—CO—R_(c), (CH₂)₀₋₂O—CO—R_(d); SR_(e) and PO(OH)(OH)₀₋₁;wherein R_(a) through R_(e), each independently of one another, ischosen from H, (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl, and(CH₂)₀₋₂-phenyl; wherein the alkyl, the alkenyl, and the alkynyl in eachcase have from zero to nine H atoms replaced by F, Cl, Br, and/or I.

In further embodiments of the compounds of formula (I), the compoundshave formula (I) in which: R₁ is a —OS(O₂)Rx, wherein Rx is alkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, each of which may be optionallysubstituted; R₂ through R₆ are, each independently of one another,chosen from H, (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl, phenyl,F, Cl, Br, I, (CH₂)₀₋₂—OR_(a), a NO₂, COOR_(b), NH—CO—R_(c), O—CO—R_(d);SR_(e) and PO(OH)(OH)₀₋₁; wherein R_(a) through R_(e), eachindependently of one another, is chosen from H, (C₁-C₄)-alkyl,(C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl, and (CH₂)₀₋₂-phenyl; wherein thealkyl, the alkenyl, and the alkynyl in each case have from zero to nineH atoms replaced by F, Cl, Br, and/or I.

In further embodiments of the compounds of formula (I), the compoundshave formula (I) in which: R₁ is —OS(O₂)CH₃; R₂ through R₅ are, eachindependently of one another, chosen from H, (C₁-C₄)-alkyl,(C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl, phenyl, F, Cl, Br, I, OR_(a), NO₂,COOR_(b), NH—CO—R_(e), O—CO—R_(d); SR_(e) and PO(OH)(OH)₀₋₁; whereinR_(a) through R_(e), each independently of one another, is chosen fromH, (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl, and (CH₂)₀₋₂-phenyl;wherein the alkyl, the alkenyl, and the alkynyl in each case have fromzero to nine H atoms replaced by F, Cl, Br, and/or I; and R₆ is H.

In further embodiments of the compounds of formula (I), the compoundshave formula (I) in which: R₁ is a —OS(O₂)CH₃; R₂ through R₅ are, eachindependently of one another, chosen from H, (C₁-C₄)-alkyl, F, Cl, Br,I, NO₂, and PO(OH)(OH)₀₋₁; wherein R_(a) through R_(e), eachindependently of one another, is chosen from H and (C₁-C₄)-alkyl; andwherein the alkyl, the alkenyl, and the alkynyl in each case have fromzero to nine H atoms replaced by F, Cl, Br, and/or I; and R₆ is H.

In further embodiments of the compounds of formula (I), the compoundshave formula (I) in which: R₁ is a —OS(O₂)CH₃; R₁ through R₅ are, eachindependently of one another, chosen from H, (C₁-C₄)-alkyl, F, Cl, Br,I, NO₂, and PO(OH)(OH)₀₋₁; wherein R_(a) through R_(e), eachindependently of one another, is chosen from H and (C₁-C₄)-alkyl; and R₆is H.

In further embodiments of the compounds of formula (I), the compoundshave formula (I) in which: R₁ is a —OS(O₂)CH₃; R₂ through R₅ are, eachindependently of one another, chosen from H, F, Cl, Br, I, NO₂, andPO(OH)(OH)₀₋₁; and R₆ is H.

In further embodiments of the compounds of formula (I), the compoundshave formula (I) in which: R₁ is —OS(O₂)CH₃; R₂ through R₅ are, eachindependently of one another, chosen from H, (C₁-C₆)-alkyl, F, Cl, Br,I, (CH₂)₀₋₂—OR_(a), NO₂, COOR_(b), NH—CO—R_(c), O—CO—R_(d); SR_(e) andPO(OH)(OH)₀₋₁; and wherein R_(a) through R_(e), each independently ofone another, are chosen from H and (C₁-C₆)-alkyl; and R₆ is H.

In the formulas for the disclosed compounds, (CH₂)₀₋₂ represents a bondwhen the subscript is zero, (CH₂) when the subscript is 1, and CH₂CH₂when the subscript is 2. Similarly, the term (CH₂)₀₋₂ in, for example,(CH₂)₀₋₂—CO—X represents CO—X, CH₂—CO—X, and (CH₂)₂—CO—X. Other recite(CH₂)₀₋₂ and similar terms, such as (CH₂)₀₋₁, (CH₂)₁₋₂, etc. The meaningof each term could be readily determined by one of ordinary skill.

The disclosed compounds include compounds of formula (I), salts, andsolvates thereof. For example, in some embodiments, the compound of thepresent invention may be a salt of a solvate.

The term “salts” is used in its broadest sense. For example, the termsalts includes hydrogen salts and hydroxide salts with ions of thepresent compound. In some embodiments, the term salt may be a subclassreferred to as pharmaceutically acceptable salts, which are salts of thepresent compounds having a pharmacological activity and which areneither biologically nor otherwise undesirable. In all embodiments, thesalts can be formed with acids, such as, without limitation, hydrogen,acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptanoate, glycero-phosphate, hemisulfate, heptanoate,hexanoate, hydrochloride hydrobromide, hydroiodide,2-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate andundecanoate. In all embodiments, the salts can be formed with bases,such as, without limitation, hydroxide, ammonium salts, alkali metalsalts such as lithium, sodium and potassium salts, alkaline earth metalsalts such as calcium, magnesium salts, aluminum salts, salts withorganic bases such as ammonia, methylamine, diethylamine, ethanolamine,dicyclohexylamine, N-methylmorpholine, N-methyl-D-glucamine, and saltswith amino acids such as arginine and lysine. Basic nitrogen-containinggroups can be quarternized with agents including lower alkyl halidessuch as methyl, ethyl, propyl and butyl chlorides, bromides and iodides;dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates;long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides; and aralkyl halides such as benzyl andphenethyl bromides.

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds of the present inventionwhich are water or oil-soluble or dispersible; which are suitable fortreatment of diseases without undue toxicity, irritation, andallergic-response; which are commensurate with a reasonable benefit/riskratio; and which are effective for their intended use. The salts can beprepared during the final isolation and purification of the compounds orseparately by reacting the appropriate compound in the form of the freebase with a suitable acid. Representative acid addition salts includeacetate, adipate, alginate, L-ascorbate, aspartate, benzoate,benzenesulfonate (besylate), bisulfate, butyrate, camphorate,camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate,glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate,DL-mandelate, mesitylenesulfonate, methanesulfonate,naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate,picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate,tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate,glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), andundecanoate. Also, basic groups in the compounds of the presentinvention can be quaternized with methyl, ethyl, propyl, and butylchlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamylsulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, andiodides; and benzyl and phenethyl bromides. Examples of acids which canbe employed to form therapeutically acceptable addition salts includeinorganic acids such as hydrochloric, hydrobromic, sulfuric, andphosphoric, and organic acids such as oxalic, maleic, succinic, andcitric. Salts can also be formed by coordination of the compounds withan alkali metal or alkaline earth ion. Hence, the present inventioncontemplates sodium, potassium, magnesium, and calcium salts of thecompounds of the compounds of the present invention and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy, phenol or similargroup with a suitable base such as the hydroxide, carbonate, orbicarbonate of a metal cation or with ammonia or an organic primary,secondary, or tertiary amine. The cations of therapeutically acceptablesalts include lithium, sodium, potassium, calcium, magnesium, andaluminum, as well as nontoxic quaternary amine cations such as ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine,pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

The term “solvates” is used in its broadest sense. For example, the termsolvates includes hydrates formed when a compound of the presentinvention contains one or more bound water molecules.

As used in the present specification the following terms have themeanings indicated:

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. Examples ofacyl groups include formyl, alkanoyl and aroyl radicals.

The term “acylamino” embraces an amino radical substituted with an acylgroup. An example of an “acylamino” radical is acetylamino (CH₃C(O)NH—).

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain, branched-chain, and cyclic unsaturated hydrocarbonradical having one or more double bonds and containing from 2 to 20,preferably 2 to 6, carbon atoms. The term “alkenyl groups” is used inits broadest sense. Alkenylene refers to a carbon-carbon double bondsystem attached at two or more positions such as ethenylene[(—CH═CH—),(—C::C—)]. For example, (C₂-C₈) alkenyl groups embracesstraight, branched, and cyclic hydrocarbon chains containing 2 to 8carbon atoms having at least one double bond, Examples of suitablealkenyl radicals include ethenyl, propenyl, iso-propenyl, butenyl,iso-butenyl, sec-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, and thelike, unless otherwise indicated.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkoxyalkoxy,” as used herein, alone or in combination, refersto one or more alkoxy groups attached to the parent molecular moietythrough another alkoxy group. Examples include ethoxyethoxy,methoxypropoxyethoxy, ethoxypentoxyethoxyethoxy and the like.

The term “alkoxyalkyl,” as used herein, alone or in combination, refersto an alkoxy group attached to the parent molecular moiety through analkyl group. The term “alkoxyalkyl” also embraces alkoxyalkyl groupshaving one or more alkoxy groups attached to the alkyl group, that is,to form monoalkoxyalkyl and dialkoxyalkyl groups.

The term “alkoxycarbonyl,” as used herein, alone or in combination,refers to an alkoxy group attached to the parent molecular moietythrough a carbonyl group. Examples of such “alkoxycarbonyl” groupsinclude methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyland hexyloxycarbonyl.

The term “alkoxycarbonylalkyl” embraces radicals having“alkoxycarbonyl”, as defined above substituted to an alkyl radical. Morepreferred alkoxycarbonylalkyl radicals are “lower alkoxycarbonylalkyl”having lower alkoxycarbonyl radicals as defined above attached to one tosix carbon atoms. Examples of such lower alkoxycarbonylalkyl radicalsinclude methoxycarbonylmethyl.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to andincluding 20, preferably 1 to 10, and more preferably 1 to 6, carbonatoms. The term “alkyl groups” is used in its broadest sense. Alkylgroups may be optionally substituted as defined herein. Examples ofalkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyland the like. For example, the O(C₁-C₈)-alkyl groups comprises thestraight O(C₁-C₈)-alkyl groups as well as the branched O(C₁-C₈)-alkylgroups. For another example, the term comprises cycloalkyl groups, asfor example, the (C₁-C₈)-alkyl groups comprises the (C₃-C₈)-cycloalkylgroups.

The term “alkylene,” as used herein, alone or in combination, refers toa saturated aliphatic group derived from a straight or branched chainsaturated hydrocarbon attached at two or more positions, such asmethylene (—CH₂—).

The term “alkylamino,” as used herein, alone or in combination, refersto an amino group attached to the parent molecular moiety through analkyl group.

The term “alkylaminocarbonyl” as used herein, alone or in combination,refers to an alkylamino group attached to the parent molecular moietythrough a carbonyl group. Examples of such radicals includeN-methylaminocarbonyl and N,N-dimethylcarbonyl.

The term “alkylcarbonyl” and “alkanoyl,” as used herein, alone or incombination, refers to an alkyl group attached to the parent molecularmoiety through a carbonyl group. Examples of such groups includemethylcarbonyl and ethylcarbonyl.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylsulfinyl,” as used herein, alone or in combination,refers to an alkyl group attached to the parent molecular moiety througha sulfinyl group. Examples of alkylsulfinyl groups includemethylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.

The term “alkylsulfonyl,” as used herein, alone or in combination,refers to an alkyl group attached to the parent molecular moiety througha sulfonyl group. Examples of alkylsulfinyl groups includemethanesulfonyl, ethanesulfonyl, tert-butanesulfonyl, and the like.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove. Examples of suitable alkyl thioether radicals include methylthio,ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio,sec-butylthio, tert-butylthio, ethoxyethylthio, methoxypropoxyethylthio,ethoxypentoxyethoxyethylthio and the like.

The term “alkylthioalkyl” embraces alkylthio radicals attached to analkyl radical. Alkylthioalkyl radicals include “lower alkylthioalkyl”radicals having alkyl radicals of one to six carbon atoms and analkylthio radical as described above. Examples of such radicals includemethylthiomethyl.

The term “alkynyl,” as used herein in its broadest sense, alone or incombination, refers to a straight-chain, branched chain hydrocarbon andcyclic unsaturated hydrocarbon radicals having one or more triple bondsand containing from 2 to 20, preferably from 2 to 6, more preferablyfrom 2 to 4, carbon atoms. “Alkynylene” refers to a carbon-carbon triplebond attached at two positions such as ethynylene (—C:::C—, —C≡C—). Forexample, (C₂-C₈)alkynyl groups embraces straight, branched, and cyclichydrocarbon chains containing 2 to 8 carbon atoms having at least onetriple bond, and the term includes but is not limited to substituentssuch as ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl,pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl,hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl, and thelike, unless otherwise indicated.

The term “amido,” as used herein, alone or in combination, refers to anamino group as described below attached to the parent molecular moietythrough a carbonyl group. The term “C-amido” as used herein, alone or incombination, refers to a —C(═O)—NR₂ group with R as defined herein. Theterm “N-amido” as used herein, alone or in combination, refers to aRC(═O)NH— group, with R as defined herein.

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,alkyl, alkylcarbonyl, aryl, arylalkenyl, arylalkyl, cycloalkyl,haloalkylcarbonyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl,heterocycle, heterocycloalkenyl, and heterocycloalkyl, wherein the aryl,the aryl part of the arylalkenyl, the arylalkyl, the heteroaryl, theheteroaryl part of the heteroarylalkenyl and the heteroarylalkyl, theheterocycle, and the heterocycle part of the heterocycloalkenyl and theheterocycloalkyl can be optionally substituted with one, two, three,four, or five substituents independently selected from the groupconsisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxy-alkyl, nitro, and oxo.

The term “aminoalkyl,” as used herein, alone or in combination, refersto an amino group attached to the parent molecular moiety through analkyl group. Examples include aminomethyl, aminoethyl and aminobutyl.The term “alkylamino” denotes amino groups which have been substitutedwith one or two alkyl radicals. Suitable “alkylamino” groups may bemono- or dialkylated, forming groups such as, for example,N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and thelike.

The terms “aminocarbonyl” and “carbamoyl,” as used herein, alone or incombination, refer to an amino-substituted carbonyl group, wherein theamino group can be a primary or secondary amino group containingsubstituents selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl radicals and the like.

The term “aminocarbonylalkyl,” as used herein, alone or in combination,refers to an aminocarbonyl radical attached to an alkyl radical, asdescribed above. An example of such radicals is aminocarbonylmethyl. Theterm “amidino” denotes an —C(NH)NH₂ radical. The term “cyanoamidino”denotes an —C(N—CN)NH₂ radical.

The term “aralkenyl” or “arylalkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “aralkoxy” or “arylalkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “aralkyl” or “arylalkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “aralkylamino” or “arylalkylamino,” as used herein, alone or incombination, refers to an arylalkyl group attached to the parentmolecular moiety through a nitrogen atom, wherein the nitrogen atom issubstituted with hydrogen.

The term “aralkylidene” or “arylalkylidene,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkylidene group

The term “aralkylthio” or “arylalkylthio,” as used herein, alone or incombination, refers to an arylalkyl group attached to the parentmolecular moiety through a sulfur atom.

The term “aralkynyl” or “arylalkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “aralkoxycarbonyl,” as used herein, alone or in combination,refers to a radical of the formula aralkyl-O—C(O)— in which the term“aralkyl,” has the significance given above. Examples of anaralkoxycarbonyl radical are benzyloxycarbonyl (Z or Cbz) and4-methoxyphenylmethoxycarbonyl (MOS).

The term “aralkanoyl,” as used herein, alone or in combination, refersto an acyl radical derived from an aryl-substituted alkanecarboxylicacid such as benzoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl),4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl,4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl, and the like. The term“aroyl” refers to an acyl radical derived from an arylcarboxylic acid,“aryl” having the meaning given below. Examples of such aroyl radicalsinclude substituted and unsubstituted benzoyl or napthoyl such asbenzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl,6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl,3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl,3-(benzyloxyformamido)-2-naphthoyl, and the like.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch rings may be attached together in a pendent manner or may be fused.The term “aryl” embraces aromatic radicals such as phenyl, naphthyl,anthracenyl, phenanthryl, and biphenyl. The aryl groups of the presentinvention can be optionally substituted with one, two, three, four, orfive substituents independently selected from the groups as definedherein.

The term “arylamino” as used herein, alone or in combination, refers toan aryl group attached to the parent moiety through an amino group, suchas N-phenylamino, and the like.

The terms “arylcarbonyl” and “aroyl,” as used herein, alone or incombination, refer to an aryl group attached to the parent molecularmoiety through a carbonyl group.

The term “aryloxy,” as used herein, alone or in combination, refers toan aryl group attached to the parent molecular moiety through an oxygenatom.

The term “arylsulfonyl,” as used herein, alone or in combination, refersto an aryl group attached to the parent molecular moiety through asulfonyl group.

The term “arylthio,” as used herein, alone or in combination, refers toan aryl group attached to the parent molecular moiety through a sulfuratom.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes —CO₂H.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H₄=derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NR, group-with R as defined herein.

The term “C-linked” as used herein, alone or in combination, refers toany substituent that is attached to the parent molecular moiety througha carbon-carbon bond.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NH— group, with R as defined herein.

The term “carbonate” as used herein, alone or in combination, refers toa —O—C(═O)OR group, with R as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxy,” as used herein, refers to —C(O)OH or thecorresponding “carboxylate” such as a carboxylic acid salt derivative orester derivative. An “O-carboxy” group refers to a RC(O)O— group, whereR is as defined herein. A “C-carboxy” group refers to a —C(O)OR groupswhere R is as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” as used herein, alone or in combination, refersto a saturated or partially saturated monocyclic, bicyclic or tricyclicalkyl radical wherein each cyclic moiety contains from 3 to 12,preferably three to seven, carbon atom ring members and which mayoptionally be a benzo fused ring system which is optionally substitutedas defined herein. Examples of such cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like.“Bicyclic” and “tricyclic” as used herein are intended to include bothfused ring systems, such as decahydronapthalene, octahydronapthalene aswell as the multicyclic (multicentered) saturated or partiallyunsaturated type. The latter type of isomer is exemplified in general bybicyclo[2,2,2]octane, bicyclo[2,2,2]octane, bicyclo[1,1,1]pentane,camphor and bicyclo[3,2,1]octane.

The term “cycloalkenyl,” as used herein, alone or in combination, refersto a partially unsaturated monocyclic, bicyclic or tricyclic radicalwherein each cyclic moiety contains from 3 to 12, preferably five toeight, carbon atom ring members and which may optionally be a benzofused ring system which is optionally substituted as defined herein.Examples of such cycloalkenyl radicals include cyclopentenyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctadienyl,-1H-indenyl and the like.

The term “cycloalkylalkyl,” as used herein, alone or in combination,refers to an alkyl radical as defined above which is substituted by acycloalkyl radical as defined above. Examples of such cycloalkylalkylradicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl,cyclopentylpropyl, cyclohexylbutyl and the like.

The term “cycloalkenylalkyl,” as used herein, alone or in combination,refers to an alkyl radical as defined above which is substituted by acycloalkenyl radical as defined above. Examples of suchcycloalkenylalkyl radicals include 1-methylcyclohex-1-enyl-,4-ethylcyclohex-1-enyl-, 1-butylcyclopent-1-enyl-,3-methylcyclopent-1-enyl- and the like.

The term “ester,” as used herein, alone or in combination, refers to acarbonyloxy —(C═O)O— group bridging two moieties linked at carbon atoms.Examples include ethyl benzoate, n-butyl cinnamate, phenyl acetate andthe like.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have either an iodo, bromo, chloro orfluoro atom within the radical. Dihalo and polyhaloalkyl radicals mayhave two or more of the same halo atoms or a combination of differenthalo radicals. Examples of haloalkyl radicals include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refersto a halohydrocarbyl group attached at two or more positions. Examplesinclude fluoromethylene (—CFH—), difluoromethylene (—CF₂—),chloromethylene (—CHCl—) and the like. Examples of such haloalkylradicals include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, perfluorodecyland the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon radical,or combinations thereof, fully saturated or containing from 1 to 3degrees of unsaturation, consisting of the stated number of carbon atomsand from one to three heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N and S may be placed at any interior position of theheteroalkyl group. Up to two heteroatoms may be consecutive, such as,for example, —CH2-NH—OCH3.

The term “heteroaryl,” as used herein, alone or in combination, refersto an aromatic five- or six-membered ring, where at least one atom isselected from the group consisting of N, O, and S, and the remainingring atoms are carbon. The five-membered rings have two double bonds,and the six-membered rings have three double bonds. The heteroarylgroups are connected to the parent molecular group through asubstitutable carbon or nitrogen atom in the ring. The term “heteroaryl”also includes systems where a heteroaryl ring is fused to an aryl group,as defined herein, a heterocycle group, as defined herein, or anadditional heteroaryl group. Heteroaryls are exemplified bybenzothienyl, benzoxazolyl, benzofuranyl, benzimidazolyl, benzthiazolylbenzotriazolyl, cinnolinyl, furyl, imidazolyl, triazolyl [e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.],tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], indazolyl,indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.], oxazolyl, isoxazolyl, purinyl, thiazolyl,isothiazolyl, thienopyridinyl, thienyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.],pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl,pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl,quinolinyl, thieno[2,3-c]pyridinyl, tetrazolyl, triazinyl, and the like.The heteroaryl groups of the present invention can be optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the groups as defined herein.

Examples of preferred heteroaryl groups include, without limitation,thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl,imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl,triazolyl, and isoxazolyl

The term “heteroaralkyl” or “heteroarylalkyl,” as used herein, alone orin combination, refers to a heteroaryl group attached to the parentmolecular moiety through an alkyl group.

The term “heteroaralkenyl” or “heteroarylalkenyl,” as used herein, aloneor in combination, refers to a heteroaryl group attached to the parentmolecular moiety through an alkenyl group.

The term “heteroaralkoxy” or “heteroarylalkoxy,” as used herein, aloneor in combination, refers to a heteroaryl group attached to the parentmolecular moiety through an alkoxy group.

The term “heteroaralkylidene” or “heteroarylalkylidene,” as used herein,alone or in combination, refers to a heteroaryl group attached to theparent molecular moiety through an alkylidene group.

The term “heteroaryloxy,” as used herein, alone or in combination,refers to a heteroaryl group attached to the parent molecular moietythrough an oxygen atom.

The term “heteroarylsulfonyl,” as used herein, alone or in combination,refers to a heteroaryl group attached to the parent molecular moietythrough a sulfonyl group.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic radical containing at least one, preferably 1 to4, and more preferably 1 to 2 heteroatoms as ring members, wherein eachsaid heteroatom may be independently selected from the group consistingof nitrogen, oxygen, and sulfur, and wherein there are preferably 3 to 8ring members in each ring, more preferably 3 to 7 ring members in eachring, and most preferably 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclicfused and benzo fused ring systems; additionally, both terms alsoinclude systems where a heterocycle ring is fused to an aryl group, asdefined herein, or an additional heterocycle group. Heterocycle groupsof the invention are exemplified by aziridinyl, azetidinyl,1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl,dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Theheterocycle groups may be optionally substituted unless specificallyprohibited.

The term “heterocycloalkenyl,” as used herein, alone or in combination,refers to a heterocycle group attached to the parent molecular moietythrough an alkenyl group.

The term “heterocycloalkoxy,” as used herein, alone or in combination,refers to a heterocycle group attached to the parent molecular groupthrough an oxygen atom.

The term “heterocycloalkyl,” as used herein, alone or in combination,refers to an alkyl radical as defined above in which at least onehydrogen atom is replaced by a heterocyclo radical as defined above,such as pyrrolidinylmethyl, tetrahydrothienylmethyl, pyridylmethyl andthe like.

The term “heterocycloalkylidene,” as used herein, alone or incombination, refers to a heterocycle group attached to the parentmolecular moiety through an alkylidene group.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl” as used herein, alone or in combination, refersto a linear or branched alkyl group having one to about ten carbon atomsany one of which may be substituted with one or more hydroxyl radicals.Examples of such radicals include hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxybutyl and hydroxyhexyl.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of this invention.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in combination, meanscontaining from 1 to and including 6 carbon atoms.

The term “mercaptoalkyl” as used herein, alone or in combination, refersto an R′SR— group, where R and R′ are as defined herein.

The term “mercaptomercaptyl” as used herein, alone or in combination,refers to a RSR′S— group, where R is as defined herein.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “null” refers to a lone electron pair.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups ordesignated subsets thereof, alone or in combination: hydrogen, carbonyl(oxo), carboxyl, lower alkyl carboxylate, lower alkyl carbonate, loweralkyl carbamate, halogen, hydroxy, amino, amido, cyano, hydrazinyl,hydrazinylcarbonyl, alkylhydrazinyl, dialkylhydrazinyl, arylhydrazinyl,heteroarylhydrazinyl, nitro, thiol, sulfonic acid, trisubstituted silyl,urea, acyl, acyloxy, acylamino, arylthio, lower alkyl, lower alkylamino,lower dialkylamino, lower alkyloxy, lower alkoxyalkyl, lower alkylthio,lower alkylsulfonyl, lower alkenyl, lower alkenylamino, lowerdialkenylamino, lower alkenyloxy, lower alkenylthio, lower alkenylsulfonyl, lower alkynyl, lower alkynylamino, lower dialkynylamino, loweralkynyloxy, lower alkynylthio, lower alkynylsulfonyl, lower cycloalkyl,lower cycloalkyloxy, lower cycloalkylamino, lower cycloalkylthio, lowercycloalkylsulfonyl, lower cycloalkylalkyl, lower cycloalkylalkyloxy,lower cycloalkylalkylamino, lower cycloalkylalkylthio, lowercycloalkylalkylsulfonyl, aryl, aryloxy, arylamino, arylthio,arylsulfonyl, arylalkyl, arylalkyloxy, arylalkylamino, arylalkylthio,arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylamino,heteroarylthio, heteroarylsulfonyl, heteroarylalkyl, heteroarylalkyloxy,heteroarylalkylamino, heteroarylalkylthio, heteroarylalkylsulfonyl,heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino,heterocycloalkylthio, heterocycloalkylsulfonyl, lower haloalkyl, lowerhaloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy,lower haloalkoxy, and lower acyloxy. Two substituents may be joinedtogether to form a fused four-, five-, six-, or seven-memberedcarbocyclic or heterocyclic ring consisting of zero to threeheteroatoms, for example forming methylenedioxy or ethylenedioxy. Anoptionally substituted group may be unsubstituted (e.g., —CH₂CH₃), fullysubstituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended. Allpendant aryl, heteroaryl, and heterocyclo moieties can be furtheroptionally substituted with one, two, three, four, or five substituentsindependently selected from the groups listed above.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo” as used herein, alone or in combination, refers to adoubly bonded oxygen ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The term “phosphonate” as used herein, alone or in combination, refersto the —P(═O)(OR)(OR1) group.

The term “phosphinate” as ues herein, alone or in combination, refers tothe —P(═O)(R)(OR1) group.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S and —S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—SO₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NH— group with R as definedherein.

The term “S-sulfonamido” refers to a —S(═O)₂NR₂, group, with R asdefined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thioether,” as used herein, alone or in combination, refers toa thio group bridging two moieties linked at carbon atoms.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NH— group, with R asdefined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NR, group with R as definedherein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂— group where X isa halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition ofsubstituted amino. Examples include trimethysilyl,tert-butyldimethylsilyl, triphenylsilyl and the like.

The term “urea,” as used herein, alone or in combination, refers to—N(R)C(═O)N(R)(R), with R as defined herein.

The term “alkyl” is used in its broadest sense. For example, the termrefers to a branched, unbranched, and cyclic saturated hydrocarbonchains comprising a designated number of carbon atoms. For example, theO(C₁-C₈)-alkyl comprises the straight O(C₁-C₈)-alkyl as well as thebranched O(C₁-C₈)-alkyl. For another example, the term comprisescycloalkyl, as for example, the (C₁-C₈)-alkyl comprises the(C₃-C₈)-cycloalkyl. In all embodiments, the term includes but is notlimited to substituents such as methyl, ethyl, propyl, iso-propyl,butyl, iso-butyl, sec-buty, tert-butyl, n-pentyl, n-hexyl, and the like,unless otherwise indicated.

The term “alkenyl” is used in its broadest sense. For example, the termalkenyl refers to branched, unbranched, and cyclic unsaturatedhydrocarbon chains comprising a designated number of carbon atoms. Forexample, (C₂-C₈)alkenyl embraces straight, branched, and cyclichydrocarbon chains containing 2 to 8 carbon atoms having at least onedouble bond, and the term includes but is not limited to substituentssuch as ethenyl, propenyl, iso-propenyl, butenyl, iso-butenyl,sec-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, and the like, unlessotherwise indicated.

The term “alkynyl” is used in its broadest sense. For example, the termalkynyl refers to branched, unbranched, and cyclic unsaturatedhydrocarbon chains comprising a designated number of carbon atoms. Forexample, (C₂-C₈)alkynyl embraces straight, branched, and cyclichydrocarbon chains containing 2 to 8 carbon atoms having at least onetriple bond, and the term includes but is not limited to substituentssuch as ethynyl, propynyl, butenyl, n-pentynyl and branchedcounterparts, n-hexynyl and branched counterparts, and the like, unlessotherwise indicated.

The term “heteroaryl,” as used herein, alone or in combination, refersto 3 to 14 membered, preferably 5 to 7 membered, unsaturatedheterocyclic rings wherein at least one atom is selected from the groupconsisting of O, S, and N. Heteroaryl are exemplified by: unsaturated 5to 14 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms,for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl,etc.]tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.;unsaturated condensed heterocyclic group containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl[e.g., tetrazolo[1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to6-membered heteromonocyclic groups containing an oxygen atom, forexample, pyranyl, furyl, etc.; unsaturated 3 to 6-memberedheteromonocyclic groups containing a sulfur atom, for example, thienyl,etc.; unsaturated 3- to 6-membered heteromonocyclic groups containing 1to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.]etc.; unsaturated condensed heterocyclic groupscontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 3 to 6-memberedheteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] andisothiazolyl; unsaturated condensed heterocyclic groups containing 1 to2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,benzothiadiazolyl, etc.] and the like. The term also embraces radicalswhere heterocyclic radicals are fused with aryl radicals. Examples ofsuch fused bicyclic radicals include benzofuryl, benzothienyl, and thelike.

For example, heteroaryl may be pyrimidinyl, pyridinyl, benzimidazolyl,thienyl, benzothiazolyl, benzofuranyl and indolinyl. Preferredheteroaryls include, without limitation, thienyl, benzothienyl, furyl,benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,tetrazolyl, oxazolyl, thiazolyl, triazolyl, and isoxazolyl

In any embodiment of the compounds of formula (I), R₂ through R₅ may bethe same, may be different, or some members of R₂ through R₅ may be thesame while the others are different. Any combination is possible.

In any embodiment of the compounds of formula (I), either R₁ or R₆ maybe SO₂CH₃. However, if R₁ is SO₂CH₃, then R₆ is H. In anotherembodiment, if R₆ is SO₂CH₃, then R₁ is chosen from H, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, phenyl, F, Cl, Br, I, (CH₂)₀₋₂—OR_(a),a NO₂, (CH₂)₀₋₂—COOR_(b), NH—(CH₂)₀₋₂—CO—R_(c), (CH₂)₀₋₂O—CO—R_(d);SR_(e) and PO(OH)(OH)₀₋₁.

In any embodiment of the compounds of formula (I) where R₆ is SO₂CH₃, R₁and/or R₅ may independently be a group or atom other than a hydrogenatom. For example, R₁ and/or R₅ may independently be chosen from(C₁-C₈)-alkyl, F, Cl, Br, I, (CH₂)₀₋₂—OR_(a), (CH₂)₀₋₂—CO—R_(f),(CH₂)₀₋₂—COOR_(g), (CH₂)₀₋₂—CO—NR_(h)R_(i), O—(CH₂)₀₋₂—CO—OR_(k),(CH₂)₀₋₂O—CO—R_(u), and (CH₂)₀₋₂PO(OR_(v))(OR_(w)). In any embodiment,R₁ and/or R₅ may independently be chosen from OR_(a), CO—R_(f),COOR_(g), CO—NR_(h)R_(i), O—CO—OR_(k), O—CO—R_(u), andPO(OR_(v))(OR_(w))₀₋₁. In some embodiments, R₁ and/or R₅ mayindependently be chosen from OH, O—CO—CH₃, O—CO—CH₂CH₃, CH₃, CH₂CH₃, andPO(OH)₂. R_(a) through R_(k) and R_(m) through R_(u), each independentlyof one another, may be chosen from H, (C₁-C₈)-alkyl, and(CH₂)₁₋₂-phenyl. In any embodiment, R_(a) through R_(k) and R_(m)through R_(u), each independently of one another, may be chosen from H,(C₁-C₄)-alkyl, and phenyl. In any embodiment, R_(a) through R_(k) andR_(m) through R_(u), each independently of one another, may be chosenfrom H and (C₁-C₃)-alkyl. R_(v) and R_(W), each independently of oneanother, may be chosen from H, (C₁-C₈)-alkyl, (C₂-C₈)-alkenyl,(C₂-C₈)-alkynyl, (CH₂)₁₋₂-phenyl. In any embodiment, R_(v) and R_(w),each independently of one another, may be chosen from H, (C₁-C₄)-alkyl,and (CH₂)₁₋₂-phenyl. In any embodiment, R_(v) and R_(w), eachindependently of one another, may be chosen from H and (C₁-C₃)-alkyl.

In any embodiment of the compounds of formula (I), alkyl, alkenyl, andalkynyl in each case may, or may not, have from zero to nine H atomsreplaced by F, Cl, Br, and/or I. In any embodiment, the phenyl in eachcase may, or may not, have from zero to five H atoms replaced by F, Cl,Br, and/or I. In any embodiment, alkyl in each case can have from zeroto four H atoms replaced by OH and/or NH₂. In any embodiment, phenyl ineach case has from zero to two H atoms replaced by NO₂ and/or(CH₂)₀₋₂CO—(C₁-C₆)-alkyl and/or (CH₂)₀₋₂CO—(C₂-C₆)-alkenyl and/or(CH₂)₀₋₂CO—(C₂-C₆)-alkynyl and/or (CH₂)₀₋₂CO—(CH₂)₀₋₂-phenyl. In anyembodiment, the phenyl in each case can have from zero to two H atomsreplaced by a NO₂ and/or CO—(C₁-C₃)-alkyl and/or CO—(CH₂)₁₋₂-phenyl.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower heteroalkyl, lowerheterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl,lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl,aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl,lower carboxyester, lower carboxamido, cyano, hydrogen, halogen,hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, loweralkylthio, arylthio, lower alkylsulfinyl, lower alkylsulfonyl,arylsulfinyl, arylsulfonyl, arylthio, sulfonate, sulfonic acid,trisubstituted silyl, N₃, NHCH₃, N(CH₃)₂, SH, SCH₃, CO₂CH₃, C(O)NH₂,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH2CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.” The term “lower” denotes the presence ofno more than six carbon atoms.

Examples of compounds of the present invention may include, but are notlimited to the following compounds listed in Table 7 below:

TABLE 7 No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

Table 8 designates the melting points of various compounds.

TABLE 8 Melting Point Compound # Structure (° C.) 11

185.5-187.8 6

282-283 60

223.5-225.6 7

173-175 62

175.6-178.8 69

145-147 70

225-226 71

100-101 72

180-181 73

138-140 74

235-236 75

>300 76

193.5-195.5 77

135.2-136.2 78

279.6-280.6 79

186.5 (dec) 80

252.5-255.5 (dec) 81

271.1-272.3 82

185.7-188.7 83

242-246 (dec) 84

253-255 (dec) 86

209-212 87

258-259 (dec)

For the above compounds that have a methylsulfonyl (—SO₂CH₃), it is alsoenvisioned by the inventors that in place of the methylsulfonyl a moietyselected from —SO₂CH₂CH₃, —SO₂CH₂CH(CH₃)₂, —CH₂SO₂CH₃, —NHSO₂CH₃ and—SO₂-cyclopropyl may be used.

A compound of the present invention, where R₆ is SO₂CH₃, may be made byreacting an acyl halide with an amine under suitable reactionconditions. In some embodiments, the reaction may be genericallyrepresented as follows:

Compounds of the present invention may also be made in accordance withthe following reaction scheme:

The compound, 2-(thiazol-2-ylcarbamoyl)phenyl methanesulfonate (11), maybe synthesized by the method described in Example 3.0.

Other compounds of the present invention may also be made in accordancewith the following reaction scheme:

The compounds 2-hydroxy-N-[4-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide(60) and 2-{[4-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenylacetate (62) may be synthesized by the method described in Example 4.0.

Other compounds of the present invention may also be made in accordancewith the following reaction scheme:

The compounds 4-{[4-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenylacetate (83), 4-hydroxy-N-[4-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide(84), 3-{[4-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenyl acetate(86), and 3-hydroxy-N-[4-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide(87), may be synthesized by the general methods described in Example5.0.

Furthermore, compounds of the present invention may also be made inaccordance with the following reaction scheme:

The compounds 4-{[5-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenylacetate (78), 3-{[5-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenylacetate (79), 4-hydroxy-N[5-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide(80) and 3-hydroxy-N-[5-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide (81)may be synthesized by the general methods described in Example 6.0.

Other compounds of the present invention may also be made in accordancewith the following reaction scheme:

The compounds 2-(5-(methylsulfonyl)thiazol-2-ylcarbamoyl)phenyl acetate(7) and 2-hydroxy-N-(5-(methylsulfonyl)thiazol-2-yl)benzamide (6), maybe synthesized by the method described in Example 7.0.

The present invention also includes a composition comprising, in acarrier, at least one compound of the present invention.

The term carrier is used in its broadest sense. For example, the termcarrier refers to any carriers, diluents, excipients, wetting agents,buffering agents, suspending agents, lubricating agents, adjuvants,vehicles, delivery systems, emulsifiers, disintegrants, absorbents,preservatives, surfactants, colorants, flavorants, and sweeteners. Insome embodiments, the carrier may be a pharmaceutically acceptablecarrier, a term narrower than carrier, because the term pharmaceuticallyacceptable carrier” means a non-toxic that would be suitable for use ina pharmaceutical composition.

The present invention also relates to a pharmaceutical compositioncomprising, in a pharmaceutically acceptable carrier, an effectiveamount of at least one compound of the invention.

The term effective amount is used in its broadest sense. The term, forexample, refers to the amount required to produce a desired effect.

In some embodiments, the compound of the invention is present in apharmaceutical composition in an effective amount for treating HCVinfection (e.g., chronic HCV infection). “Treating HCV infection” mayrefers to: (i) preventing HCV infection from occurring in an animal thatmay be predisposed to HCV infection but has not yet been diagnosed ashaving it; (ii) inhibiting or slowing HCV infection, e.g. arresting itsdevelopment; (iii) relieving chronic infection, e.g. causing itsregression; (iv) improving a symptom in a subject having chronicinfection; and/or (v) prolonging the survival of a subject havingchronic infection.

The compositions of the present invention may be formulated as solid orliquid dosage forms, or as pastes or ointments, and may optionallycontain further active ingredients.

A pharmaceutical composition of the present invention comprises apharmaceutically acceptable carrier, which is not particularly limited,and includes a wide range of carriers known to those of ordinary skillin the art, and including wetting or dispersing agents (U.S. Pat. No.5,578,621, which is incorporated herein by reference), starchderivatives (U.S. Pat. No. 5,578,621, which is incorporated herein byreference), excipients, and the like. Tablet embodiments may optionallycomprise a coating of a substance that constitutes an enteric coating,i.e., a coating that substantially insoluble in gastric secretion butsubstantially soluble in intestinal fluids.

Pharmaceutical compositions comprising the compounds of the presentinvention are in some embodiments formulated for oral administration andare optionally in the form of a liquid, for example an emulsion or asolution or a suspension in water or oil such as arachis oil, or otherliquid. Formulations of non-aqueous micellar solutions may be preparedaccording to the method disclosed in U.S. Pat. No. 5,169,846, which isincorporated herein by reference. Alternatively, tablets can bemanufactured, for example, by performing the following steps: wetgranulation; drying; and compression. Film coating may generally beperformed with organic solvents.

The present invention is a method, comprising administering to a subjectat least one compound of the present invention in an amount in aneffective amount for treating HCV infection (e.g., chronic HCVinfection). In some embodiments, the method, comprising administering toa subject at least one pharmaceutical composition which comprises atleast one compound of the present invention in an amount in an effectiveamount for treating HCV infection (e.g., chronic HCV infection).

In some embodiments, the subject is chosen from animals. In someembodiments, the subject is chosen from mammals. In some embodiments,the subject is chosen from pets, such as mice, dogs, cats, etc. In someembodiments, the subject is chosen from humans.

In some embodiments, the invention provides a method of treating a viralinfection in a subject, comprising administering to the subject at leastone dose of an effective amount of at least one compound of the presentinvention. In some embodiments, the invention provides a method oftreating a viral infection in a subject, comprising administering to thesubject at least one dose of an effective amount of at least onepharmaceutical composition comprising, in a pharmaceutically acceptablecarrier, at least one compound of the present invention.

In some embodiments the antiviral treatment or prophylactic dosages ofthe compound of the present invention may depend upon the weight of thesubject, and may be inferred by one of ordinary skill without undueexperimentation by reference to the following examples, which are setforth for purposes of illustration and are not intended to be limiting.

The inventive compounds and compositions may be administered locally orsystemically by any means known to an ordinarily skilled artisan. Forexample, the inventive compounds and compositions may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir in dosage formulationscontaining conventional non-toxic pharmaceutically acceptable carriers,adjuvants and vehicles. The term parenteral as used herein includessubcutaneous, intravenous, intraarterial, intramuscular,intraperitoneal, intrathecal, intraventricular, intrasternal,intracranial or intraosseous injection and infusion techniques. Theexact administration protocol will vary depending upon various factorsincluding the age, body weight, general health, sex and diet of thepatient; the determination of specific administration procedures wouldbe routine to an ordinarily skilled artisan.

Dose levels on the order of about 0.1 to about 100 mg/kg of the activeingredient compound are useful in the treatment of the above conditions(e.g., 0.1 mg/kg-day). In some embodiments, the amounts range from about1 to about 10 mg/kg, and in other embodiments, the amounts range fromabout 2 to about 5 mg/kg. The specific dose level for any particularpatient will vary depending upon a variety of factors, including theactivity and the possible toxicity of the specific compound employed;the age, body weight, general health, sex and diet of the patient; thetime of administration; the rate of excretion; drug combination; theseverity of the particular disease being treated; and the form ofadministration. Typically, in vitro dosage-effect results provide usefulguidance on the proper doses for patient administration. Studies inanimal models are also helpful. The considerations for determining theproper dose levels are well known in the art.

Any administration regimen for regulating the timing and sequence ofdrug delivery can be used and repeated as necessary to effect treatment.Such regimen may include multiple uses or preadministration and/orco-administration and/or postadministration with food, liquid, or water.

The present invention also relates to a kit, comprising, in acompartment, at least one pharmaceutical composition comprising, in apharmaceutically acceptable carrier, an effective amount of at least onecompound of the invention. In some embodiments, the kit furthercomprises written instructions for administering the pharmaceuticalcomposition. In some embodiments, written instructions for administeringconcern indications noted elsewhere in this disclosure. In someembodiments, written instructions for administering concern anadministration regimen noted elsewhere in this disclosure.

The kit could take any form. By way of example, a kit includes one ormore containers for storing a pharmaceutical composition. In someembodiments, a container contains written instructions for administeringthe pharmaceutical composition. In some embodiments, a containercontains is the substrate for the written instructions for administeringthe pharmaceutical composition. In some embodiments, the writteninstructions for administering the pharmaceutical composition areaffixed to a container, for example, as in a container for filling aprescription sometimes has written instructions affixed on a surface.

In some embodiments, the compound of the present invention may exhibitselective antiviral activity. The term “selective antiviral” as usedherein means that, at dosages effective for the prevention or treatmentof a viral disease, the activity is more antiviral than antibacterial,antifungal, or antiparasite, and gut flora of the subject is notdisrupted to levels expected with broad spectrum antibiotics. Forexample, the effective dosage for antiviral treatment (e.g., reducingviral load at least about 2 times) may not reduce bacterial, fungal, orparasite levels in the gut (e.g., more than about 2 times)

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andits examples be considered as exemplary only, with a true scope andspirit of the invention being indicated by what may eventually beclaimed.

EXAMPLES 1. Materials and Methods 1.1 Materials

Lamivudine (LMV) and adefovir dipovoxil (ADV), and 2′-C-methyl cytidinewere purchased from Moraveck Biochemicals, Inc. (La Brea, Calif. USA).Recombinant human interferon alpha 2b (IFN) was purchased from PBLBiomedical Laboratories (Piscataway, N.J. USA). All other test compounds(FIG. 1) were provided by Romark Laboratories, L.C. Human serum(heat-inactivated, mixed gender, lot BRH125374) was purchased fromBioreclamation, Inc. (Hicksville, N.Y.).

1.2. HBV Studies 1.2.1. Antiviral Assays

HBV antiviral assays were conducted as previous described (Korba andGerin, 1992). Briefly, confluent cultures of 2.2.15 cells weremaintained on 96-well flat-bottomed tissue culture plates (confluence inthis culture system is required for active, high levels of HBVreplication equivalent to that observed in chronically-infectedindividuals (Sells, et al., 1988; Korba and Gerin, 1992). Cultures weretreated with nine consecutive daily doses of the test compounds. HBV DNAlevels were assessed by quantitative blot hybridization 24 hr. after thelast treatment. Cytotoxicity was assessed by uptake of neutral red dye24 hr. following the last treatment.

1.2.2. Activity Against Drug-Resistant HBV Mutants

Activity against LMV-resistant (Allen et al., 1998) and ADV-resistant(Angus et al., 2003) HBV mutants was performed in a 5-day assay using atransient transfection method as previously described (Iyer et al.,2004). Antiviral activity was determined by quantitative Southern blothybridization of intracellular HBV DNA replication intermediates (HBVRI).

1.2.3. Production of HBV Proteins

Cultures of 2.2.15 cells were treated under standard procedures andsemi-quantitative EIA-based analysis of HBV proteins was performed aspreviously described (Korba and Gerin, 1995), except that HBeAg wasanalyzed ETI-EBK Plus® (DiaSorin, Inc., Stillwater, Minn. USA). Sampleswere diluted (2 to 10-fold) to bring levels into the dynamic responseranges of the EIA's. HBsAg, and HBeAg were analyzed from culture mediumsamples and HBcAg was analyzed from intracellular lysates. IntracellularHBV RNA was assessed by quantitative northern blot hybridization (Korbaand Gerin, 1995).

1.3. HCV Studies

Antiviral activity of test compounds was assessed in a 3-day assay usingthe stably-expressing HCV replicon cell line, AVA5 (sub-genomic CON1,genotype 1b) (Blight et al., 2000) maintained as sub-confluent cultureson 96-well plates as previously described (Okuse et al., 2005).Antiviral activity was determined by blot hybridization analysis ofintracellular HCV RNA (normalized to the level of cellular B-actin RNAin each culture sample) and cytotoxicity was assessed by neutral red dyeuptake after 3 days of treatment. Additional studies were performedusing Huh7 cells containing another HCV replicon, H/FL-Neo, a genotype1a full length construct (Blight et al., 2003). For studies involvinghuman serum, standard culture medium (which contains 10% fetal bovineserum) and assay conditions were maintained.

1.4. Presentation of Results

EC₅₀, EC₉₀ and CC₅₀ values (±standard deviations [S.D.]) were calculatedby linear regression analysis using data combined from all treatedcultures (Korba and Gerin, 1992; Okuse et al., 2005). EC₅₀ and EC₉₀ aredrug concentrations at which a 2-fold, or a 10-fold depression ofintracellular HBV DNA or HCV RNA (relative to the average levels inuntreated cultures), respectively, was observed. CC₅₀ is the drugconcentration at which a 2-fold lower level of neutral red dye uptake(relative to the average levels in untreated cultures) was observed.Selectivity index (S.I.) was calculated as CC₅₀/EC₉₀ for HBV assays andCC₅₀/EC₅₀ for HCV assays. EC₉₀ values were used for calculation of theS.I. in HBV assays since at least a 3-fold depression of HBV DNA levelsis typically required to achieve statistical significance in this assaysystem (Korba and Gerin, 1992). For combination treatments, EC₅₀, EC₉₀,CC₅₀ and S.I. are presented for the first compound listed. The molarratio of the compounds in each combination is also indicated.

2. Results 2.1. Hepatitis B Virus (HBV) 2.1.1. Activities of Compoundsand Combinations in 2.2.15 Cell Cultures

NTZ and its active metabolite, TIZ, exhibited selective inhibition ofintracellular HBV replication and extracellular virus production by2.2.15 cells (Table 1). Several other thiazolides (see Table 1) werealso effective inhibitors of HBV replication in this assay system.Combinations of NTZ with either of two drugs licensed for anti-HBVtherapy, lamivudine (LMV) and adefovir dipovoxil (ADV), demonstratedsynergistic interactions when used to treat 2.2.15 cells (Table 1, FIGS.2A and 2B). The anti-HBV assays were conducted under confluence as thisprovides the conditions for optimal HBV replication (Sells, et al.,1988; Korba and Gerin, 1992). While under the conditions of theantiviral assay NTZ displayed minimal cytotoxicity (>100 μM, Table 1),cytotoxicity of NTZ in rapidly dividing cultures of 2.2.15 cells washigher (20±1.3 μM).

2.1.2. Activity of NTZ and RM4850 Against Drug-Resistant HBV Mutants

NTZ and RM4850 were effective inhibitors of several HBV LMV-resistantand one ADV-resistant constructs in transient transfection assays inHuh7 cells (Table 2). No significant differences in potency of thesethiazolides relative to that observed for wild-type HBV were observedfor any of the drug-resistant viruses tested.

2.1.3. Effect of NTZ on Production of HBV Proteins

Unlike most viruses (including HCV), HBV RNA transcription and proteinproduction are effectively separated from viral genome replication dueto the presence of a long-lived population of covalently-closed viraltemplate genomes in the host cell nucleus (cccDNA) (see Locarnini, 2004for a review). Intracellular HBV replication takes place in viralnucleocapsids located in the cytoplasm. As a result, most compounds thatinhibit HBV DNA replication (e.g. nucleoside analogues), do nottypically alter HBV protein production, especially in cell culture.

Suspecting a novel mechanism of action of NTZ against HBV, we conductedstudies to determine if the drug inhibited the production of major HBVproteins. As assessed by semi-quantitative EIA, NTZ reduced the levelsof extracellular HBV surface and e antigens (HBsAg, HBeAg), as well asthe levels of intracellular HBV nucleocapsid core antigen (HBcAg) in adose-dependent manner (Table 3, FIG. 3). The potency of NTZ againstHBsAg and HBeAg was similar to that observed against HBV virionproduction in the same experiment. The relative potency of NTZ againstintracellular HBcAg was similar to that observed for the inhibition ofintracellular HBV DNA replication. No quantitative interference with theability of the EIAs to detect HBV proteins was observed in samples fromcontrol cultures to which 10 μM NTZ was added (data not shown).

NTZ did not induce a reduction in intracellular HBV RNA as assessed byNorthern blot hybridization (Table 3, FIG. 3). In the same experiment,LMV did not affect the levels of HBV proteins or HBV RNA despiteinducing significant reductions in HBV virion production andintracellular HBV DNA replication (Table 3).

2.2. Hepatitis C Virus (HCV) 2.2.1. Activities of Compounds andCombinations in HCV Replicon Cell Cultures

NTZ and TIZ selectively reduced intracellular HCV replication in AVA5cells (Table 4). Both compounds were more cytotoxic in this cell linethan in 2.2.15 cells, but the compounds were also much more potentagainst HCV replication. Combinations of NTZ or TIZ with eitherrecombinant human interferon alpha 2b (IFNα), or an NS5B (HCVpolymerase) inhibitor, 2′-C-methyl cytidine (2′CmeC, Pierra, et al.2005), exhibited synergistic interactions against HCV replication (Table4, FIGS. 2C and 2D).

Only two of the other thiazolides, RM4832 and RM4863, exhibited activityagainst HCV (Table 4). Antiviral activities of NTZ, TIZ and RM4832against a full length genotype 1a replicon (Blight, et al. 2003) wereequivalent to that observed for AVA5 cells (genotype 1b) (Table 4).

2.2.2. Effect of Pre-Treating with NTZ Before Combination Treatments

Based on observations in early clinical trials using NTZ with pegylatedinterferon, we evaluated the in vitro effect of a regimen consisting of3 days treatment with NTZ followed by 3 days of a combination of NTZplus IFNα. Pre-treatment with NTZ monotherapy improved the potency ofcombination treatment with NTZ plus IFNα by approximately 3-fold (Table5, FIG. 2 panels E and F). Pre-treatment did not, however, affect thepotency of combination treatment with 2′CmeC (Table 5).

2.2.3. Effect of Human Serum on Anti-HCV Potency and Cytotoxicity of TIZin Cells

NTZ and its circulating metabolite, TIZ, are highly bound (>99%) toplasma proteins in human serum. To evaluate the effect of human serum onthe anti-HCV potency and cytotoxicity of TIZ, human serum was added tothe culture medium at various concentrations (Table 6). The CC₅₀, EC₅₀,and EC₉₀ of TIZ increased with increasing concentrations of human serumup to 20%. The EC₅₀ and EC₉₀ in the presence of 30% human serum weresimilar to those at 20% human serum (a plateau effect) suggesting thatmaximum extent of protein binding had been reached. The levels of HCVand B-actin RNA in untreated cultures were similar at differentconcentrations of human serum up to 30% (data not shown). Higherconcentrations of human serum significantly lowered cell viability (datanot shown). In the below tables, RM4863 is the same as compound 6 ofTable 7.

TABLE 1 Relative potency (μM) of test compounds against HBV replicationin 2.2.15 cell cultures. Extracellular Intracellular Selectivity virionDNA HBV RI* Index Compound CC₅₀ EC₅₀ EC₉₀ EC₅₀ EC₉₀ Virion RI LMV 2347 ±88 0.05 ± 0.01 0.15 ± 0.02 0.16 ± 0.03 0.55 ± 0.06 15646 4267 ADV >300^(#) 1.0 ± 0.2 3.0 ± 0.3 >100 NTZ >100 0.12 ± 0.02 0.83 ± 0.09 0.59± 0.07 2.1 ± 0.2 >121 >48 TIZ >100 0.15 ± 0.02 0.58 ± 0.06 0.46 ± 0.051.2 ± 0.2 >172 >83 RM4832 >100 1.2 ± 0.1 4.0 ± 0.3 2.9 ± 0.3 8.7 ±1.0 >25 >12 RM4848 >100 0.37 ± 0.07 1.7 ± 0.2 >58 RM4850 >100 0.33 ±0.07 0.83 ± 0.10 0.90 ± 0.10 2.0 ± 0.2 >120 >51 RM4851 >100 >10^(#)>10^(#) >10^(#) >10^(#) — — RM4852 >100 1.0 ± 0.1 3.3 ± 0.3 2.7 ± 0.36.3 ± 0.7 >30 >16 RM4863 >100 >10  >10  >10  >10  — — NTZ + LMV,50:1 >100  0.06 ± 0.005 0.16 ± 0.02 >625 NTZ + ADV, 3:1 >100  0.03 ±0.004 0.11 ± 0.02 >909 *HBV RI, intracellular HBV RNA replicationintermediates ^(#)no significant cytotoxic or antiviral activityobserved up to indicated concentration.

TABLE 2 Relative potency (μM) of test compounds against drug-resistantHBV mutants in cell cultures. Adefovir Nitazoxanide Lamivudine dipovoxilRM4850 HBV Mutant EC₅₀ EC₉₀ EC₅₀ EC₉₀ EC₅₀ EC₉₀ EC₅₀ EC₉₀ Wild-type 0.21± 0.03 0.77 ± 0.09 0.2 ± 0.1 0.9 ± 0.2 2.0 ± 0.2 7.0 ± 0.8 0.73 ± 0.082.0 ± 0.3 M204V 0.15 ± 0.02 0.70 ± 0.08  >100^(#)  >100^(#) 1.5 ± 0.27.2 ± 0.8 0.80 ± 0.10 2.1 ± 0.3 M204I 0.31 ± 0.05 1.0 ± 0.2 >100 >1002.5 ± 0.3 8.5 ± 1.0 1.0 ± 0.2 2.4 ± 0.3 L180M 0.23 ± 0.03 0.80 ± 0.09 16 ± 2.0  46 ± 5.6 2.6 ± 0.3 7.3 ± 0.8 0.83 ± 0.09 2.2 ± 0.2L180M/M204V 0.18 ± 0.02 0.72 ± 0.09 >100 >100 2.5 ± 0.3 7.6 ± 0.8 0.87 ±0.11 2.1 ± 0.3 N236T 0.28 ± 0.03 0.85 ± 0.10 0.3 ± 0.1 1.2 ± 0.2  11 ±1.3  32 ± 3.6 0.67 ± 0.08 2.2 ± 0.2 ^(#)no significant antiviralactivity observed up to indicated concentration.

TABLE 3 Relative potency (μM) of NTZ and lamivudine against HBVreplication and protein levels in 2.2.15 cell cultures. NitazoxanideLamivudine EC₅₀ EC₉₀ EC₅₀ EC₉₀ Virion 0.19 ± 0.02 0.58 ± 0.04 0.05 ±0.01 0.15 ± 0.02 production HBV R.I. 0.73 ± 0.06 2.2 ± 0.3 0.16 ± 0.020.56 ± 0.07 HBV RNA — — — — HBsAg 0.22 ± 0.03 1.0 ± 0.1 — — HBeAg 0.26 ±0.02 1.3 ± 0.1 — — HBcAg 1.1 ± 0.1 3.0 ± 0.2 — —

TABLE 4 Relative potency (μM) of test compounds against HCV replicationin replicon cells. Compound CC₅₀ EC₅₀ EC₉₀ Selectivity Index Genotype 1breplicon IFNα >10000^(#)*   1.9 ± 0.2*  8.9 ± 0.9* >5263 2′CmeC >300 1.6± 0.2 8.3 ± 0.7 >188 NTZ 38 ± 1.8 0.21 ± 0.03 0.93 ± 0.11 181 TIZ 15 ±1.2 0.15 ± 0.02 0.81 ± 0.92 100 RM4832 98 ± 3.2 4.9 ± 0.5  20 ± 1.9 20RM4848 15 ± 0.1  >20^(#)  >20^(#) — RM4850 2.3 ± 0.2  >20 >20 — RM48515.6 ± 0.3  >20 >20 — RM4852 6.7 ± 0.4  >20 >20 — RM4863 2.8 ± 0.3   0.04± 0.005 0.59 ± 0.07 74 2′CmeC + IFNα, 1:1 >300  0.67 ± 0.007 2.3 ±0.3 >448 NTZ + IFNα, 1:10 33 ± 1.3  0.06 ± 0.008 0.25 ± 0.03 550 NTZ +2′CmeC, 1:10 35 ± 1.5  0.07 ± 0.005 0.28 ± 0.02 500 TIZ + IFNα, 1:10 17± 1.3 0.07 ± 0.01 0.22 ± 0.03 245 TIZ + 2′CmeC, 1:10 18 ± 1.1  0.06 ±0.004 0.19 ± 0.02 300 Genotype 1a replicon IFNα >10000  2.1 ± 0.2 9.4 ±0.9 >4762 2′CmeC >300 1.8 ± 0.2 8.1 ± 0.8 >167 NTZ 49 ± 1.5 0.33 ± 0.051.1 ± 0.1 149 TIZ 14 ± 0.2 0.25 ± 0.03 1.0 ± 0.1 56 RM4832 88 ± 2.1 2.8± 0.3 9.4 ± 1.1 31 *concentrations for interferon are expressed in‘IU/ml. ^(#)no significant cytotoxic or antiviral activity observed upto indicated concentration.

TABLE 5 Effect of NTZ montherapy pretreatment on combination therapy.Treatment (6 days total duration) EC₅₀ EC₉₀ IFNα 1.7 ± 0.2  7.8 ± 0.82′CmeC 1.3 ± 0.2  5.8 ± 0.9 NTZ 0.20 ± 0.02  0.92 ± 0.10 NTZ + IFNα,1:10 0.09 ± 0.010 0.24 ± 0.04 NTZ montherapy (3 days), then 0.03 ± 0.004 0.09 ± 0.011 NTZ + IFNα (3 days) NTZ + 2′CmeC, 1:10 0.05 ± 0.007 0.17 ±0.03 NTZ montherapy (3 days), then 0.06 ± 0.005 0.15 ± 0.02 NTZ + 2′CmeC(3 days) * Values are expressed as μM concentrations of drug (firstnamed drug in the case of combinations).

TABLE 6 Relative potency (μM) of TIZ against HCV replication in thepresence of human serum. Concentration of human serum (%) EC₅₀ EC₉₀ CC₅₀0 0.25 ± 0.01 0.98 ± 0.04 28 ± 0.9 2.5 0.48 ± 0.02 1.1 ± 0.1 65 ± 1.4 50.64 ± 0.05 2.3 ± 0.1 97 ± 3.9 10 1.1 ± 0.1 3.0 ± 0.2 >100 15 2.7 ± 0.315 ± 2.0 >100 20 9.4 ± 0.8 27 ± 2.2 >100 30 9.3 ± 0.9 32 ± 3.0 >100Table 9 presents data from the primary HCV replicon cell assay.

TABLE 9 PRIMARY ASSAY CC50 EC50 EC90 Compd # (uM) (uM) (uM) SI 60 2.80.038 0.585 74.0 60 28.0 0.108 0.654 259.0  6 43.0 1.5 5.2 29.0 75 53.02.1 8.1 25.0 75 & 11 >100.0 1.3 5.0 >77 @10:1  7 20.0 >10.0 >10.062 >100.0 >10.0 >10.0 11 >100.0 >10.0 >10.0Table 10 presents data from the secondary HCV replicon cell assays usinggenotypes 1B and 1A.

TABLE 10 SECONDARY ASSAY, SECONDARY ASSAY, GENOTYPE 1B GENOTYPE 1A CC50EC50 EC90 CC50 EC50 EC90 Compd # (uM) (uM) (uM) SI (uM) (uM) (uM) SI6 >10.0 0.89 8.8 >11.1 >10.0 0.8 3.4 >12.3 75 54.0 2.1 7.9 26.0 56.0 2.88.5 20.0

3.0 Synthesis of 2-(thiazol-2-ylcarbamoyl)phenyl methanesulfonate (11)

The compound, 2-(thiazol-2-ylcarbamoyl)phenyl methanesulfonate (11), wasprepared according to the following synthetic scheme:

3.1 Synthesis of 2-(1,3-thiazol-2-ylcarbamoyl)phenyl acetate (501)

2-(Acetyloxy)-benzoic acid (500, 1.80 g, 10.0 mmol) was placed in a 250mL round bottom flask equipped with a stirbar, vacuum adapter andseptum. Ether (100 mL) and pyridine (1.00 mL, 12.4 mmol) were added tocreate a clear, colorless solution, which was cooled to zero in an icebath before thionyl chloride (875 μL, 12.0 mmol) was added dropwise overca. 30 sec. A thick white precipitate formed upon the addition of eachdrop. The reaction mixture was stirred for 90 minutes at 0° C. beforebeing filtered through paper, and removing the solvents in vacuo. Sodiumbicarbonate (3.42 g, 40.7 mmol) and 1,3-thiazol-2-amine (1.00 g, 10.0mmol) were weighed into a 250 mL round bottom flask and water (30 mL)and ethyl acetate (30 mL) were added to form a colorless biphase, whichwas stirred rapidly. The crude acid chloride was suspended in ethylacetate (10 mL) and added dropwise to the rapidly stirring biphase. Theresulting biphase was capped lightly and stirred rapidly at roomtemperature for 2 hours. The biphase layers were separated, and theaqueous was extracted twice with ethyl acetate. The combined organicswere washed with brine, dried with MgSO4, filtered, and concentrated togive 501 (1.36 g, 52%) as a colorless powder, which was used withoutpurification.

Data for 501: ¹H-NMR (400 MHz, DMSO-d6) d 12.58 (br s, 1H), 7.77 (dd,J=7.4, 1.8 Hz, 1H), 7.62 (ddd, J=7.7, 7.7, 1.8 Hz, 1H), 7.54 (d, J=3.6Hz, 1H), 7.40 (ddd, J=7.7, 7.7, 1.4 Hz, 1H), 7.28 (d, J=3.6 Hz, 1H),7.27 (dd, J=7.7. 1.4 Hz), and 2.22 (s, 3H) ppm; MS (ESI+) m/z (rel.intensity): 263.2 (5), 221.2 (40), 163.1 (10), 143.1 (10), 121.1 (40),101.0 (100) m/z.

3.2 Synthesis of 2-hydroxy-N-1,3-thiazol-2-ylbenzamide (502)

2-(1,3-thiazol-2-ylcarbamoyl)phenyl acetate (501, 663.3 mg, 2.53 mmol)was added to a 25 mL round bottom flask equipped with a stirbar and awater-jacketed condenser. The headspace was replaced with dry nitrogen,and concentrated hydrochloric acid (15.0 mL) was added in a singleportion. The suspension was heated to 50° C., and stirred well. Thesuspended solids dissolved to form a clear colorless solution beforesolids precipitate from the reaction mixture, which was then cooled inan ice bath, and the solids were filtered on a medium frit and washedwith a large portion of water. The filter cake wash washed through thefrit with methanol, collected, and the solvent was removed in vacuo togive 502 (481.5 mg, 86%) as a colorless solid.

Data for 502: ¹H-NMR (400 MHz, DMSO-d6) d 12.07 (br s, 2H), 7.99 (dd,J=7.9, 1.5 Hz, 1H), 7.55 (d, J=3.8 Hz, 1H), 7.45 (br t, J=7.5 Hz), 7.27(br d, J=2.7 Hz), and 6.9-7.05 Hz (m, 2H); MS (ESI+) m/z (rel.intensity): 221.2 (15), 121.1 (50), 101.0 (100).

3.3 Synthesis of 2-(1,3-thiazol-2-ylcarbamoyl)phenyl methanesulfonate(11)

2-hydroxy-N-1,3-thiazol-2-ylbenzamide (502, 267.1 mg, 1.21 mmol) wasplaced into a 10 mL round bottom flask equipped with a stirbar and aseptum with a dry nitrogen inlet. Dichloromethane (5.0 mL) andtriethylamine (500 μL, 3.59 mmol) were added to form a light pinksolution. Methanesulfonyl chloride (100 μL, 1.3 mmol) in dichloromethane(ca. 1.0 mL) was added dropwise to the stirring solution over ca. 30seconds, and the reaction was stirred at room temperature for ca. 20minutes before being quenched into saturated NaHCO₃, and extracted withdichloromethane. The combined organics were washed with brine, driedover MgSO₄, filtered, and concentrated in vacuo. The crude product wasrecrystallized from hexanes/ethyl acetate to yield (284 mg, 78%) of 11as a colorless crystalline solid. Example 11(2-thiazol-2-ylcarbamoyl)phenyl methanesulfonate) has the empiricalformula C₁₁H₁₀N₂O₄S and a molecular weight of 298.34.

Data for 11: mp=185.5-187.8° C.; ¹H-NMR (400 MHz, DMSO-d6) d 12.63 (brs, 1H), 7.76 (dd, J=7.9, 1.7 Hz, 1H), 7.67 (ddd, J=7.8, 7.8, 1.7 Hz,1H), 7.55 (d, J=3.5 Hz, 1H), 7.48-7.53 (m, 1H), 7.30 (d, J=3.5 Hz, 1H),and 3.35 (s, 3H) ppm; MS (ESI+) m/z (rel. intensity): 299.1 (90), 231.2(20), 220.2 (100), 199.1 (20), 121.1 (10), 100.1 (20), 56.0 (40).

4.0 Synthesis of 2-hydroxy-N-(4-(methylsulfonyl)thiazol-2-yl)benzamide(60)

The compound, 2-hydroxy-N-[4-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide(60), was prepared according to the following synthetic scheme:

4.1 Synthesis of tert-butyl 4-(methylthio)thiazol-2-ylcarbamate (504)

N-tert-butoxycarbonylthiourea (503, 0.841 g, 4.77 mmol, preparedaccording to Schiavi, B.; Ahond, A.; Poupat, C.; Potier, P. Synth.Commun. 2002, 32, 1671) was suspended in ethanol (7.0 mL) and cooled inan ice bath. A solution of S-methyl bromoethanethioate (1.371 g, 5.0582mmol, prepared according to Praveen Rao, P. N.; Amini, M.; Li, H.;Habeeb, A. G.; Knaus, E. E. J. Med. Chem. 2003, 46, 4872-82) in ethanol(7.0 mL) was added dropwise over 3 minutes. The suspension turnedhomogeneous at the end of the addition, the bath was removed, and thereaction was stirred at room temperature. The solvent was removed, andthe crude material was partitioned between dichloromethane and water.The organics were washed with water and brine. The combined aqueouslayers were back-extracted with dichloromethane, and the combinedorganics were dried with anhydrous MgSO₄, filtered, and concentrated invacuo to an orange glass (stench). The crude material was adsorbed ontoca. 5 g silica gel with ethyl acetate, and flushed through a plug ofsilica gel with hexanes (discarded) followed by 9:1 hexanes:ethylacetate. The eluent was evaporated in vacuo to yield 504 (589 mg, 50%)as a colorless solid.

Data for 504: ¹H-NMR (400 MHz, CDCl₃) d 8.93 (br s, 1H), 6.40 (s, 1H),2.45 (s, 3H), and 1.47 (s, 9H) ppm; ¹³C-NMR (100 MHz, CDCl₃) d 160.3,151.3, 145.4, 105.7, 82.8 (br), 28.2, and 16.2 ppm; MS (ESI+) m/z (rel.intensity): 191.1 (100, M-(CH₃)₂C═CH₂ ⁺), 173.1 (20), 147.1 (70), 120.0(10), and 105.0 (10) m/z. MS (ESI−) m/z (rel. intensity): 245.2 (15,M−H⁻), 171.1 (25), 145.1 (100), 103.0 (20), and 97.0 (20) m/z.

4.2 Synthesis of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate (506)

5-bromo-1,3-thiazol-2-amine hydrobromide (505, 6.5150 g, 25.062 mmol)and 4-dimethylaminopyridine (69.9 mg, 0.572 mmol) were combined under anatmosphere of dry N2, and tetrahydrofuran (40 mL) and triethylamine (15mL) were added to form a thick off-white suspension. A solution ofdi-tert-butyldicarbonate (6.0546 g, 27.742 mmol) in tetrahydrofuran (24mL) was added to the above suspension, and the resulting slurry wasstirred at room temperature for 4 h. The reaction mixture was thenpoured onto water (100 mL), and the aqueous was extracted with ethylacetate. The combined organics were washed with saturated NaHCO₃solution, brine, dried over MgSO4, filtered, and the solvent was removedin vacuo. The crude product was adsorbed onto silica gel, and elutedthrough a plug of silica gel with 9:1 hexanes:ethyl acetate. The eluentwas collected, and evaporated to give 506 (5.42 g, 78%) as a colorlesscrystalline solid.

Data for 506: ¹H NMR (400 MHz, DMSO-d6) d 12.75 (br s, 1H), 7.44 (s,1H), and 1.48 (s, 9H) ppm. ¹³C NMR (100 MHz, DMSO-d₆) δ 160.1, 152.9(br), 139.0, 100.5, 81.7, and 27.8 ppm. MS (ESI+) m/z (rel. intensity):225.1 (100, M⁸¹Br—(CH₃)₂C═CH₂ ⁺), 223.1 (100, M⁷⁹Br—(CH₃)₂C═CH₂ ⁺).

4.3 Synthesis of tert-butyl (4-bromo-1,3-thiazol-2-yl)carbamate (507)

Tetrahydrofuran (160 mL) and N,N-diisopropylamine (14 mL, 97 mmol) werecombined in a 3-neck 500 mL RBF equipped with a stirbar, septum, and aninternal temperature probe. The resulting solution was cooled to 0.8°C., and n-butyllithium in hexanes (2.50 M, 38 mL, 95 mmol) was addedslowly over ca. 5 min to produce a light yellow solution (T_(int)max=10° C.), which was stirred and allowed to re-cool to near 0° C. Asolution of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate, 506 (8.74 g,31.3 mmol) in tetrahydrofuran (30.0 mL) was added dropwise to the abovesolution over 16 min (T_(int) varied from 0.9° C. to a maximum of 7°C.). The now deep brown reaction mixture was stirred for 15 min beforebeing quenched with water (13 mL), and stirred for an additional 5minutes. Aqueous saturated NH₄Cl (250 mL) and ethyl acetate (250 mL)were added, and the layers were separated. The aqueous was extractedwith ethyl acetate, and the combined organics were washed with brine,dried with MgSO₄, filtered, and concentrated in vacuo. The crudematerial was adsorbed onto silica gel with ethyl acetate, and elutethrough a plug of silica gel with 2 liters of 9:1 hex:EtOAc The eluentwas collected, and the solvents were removed to give 507 (8.41 g, 96%)as a colorless solid.

Data for 507: ¹H NMR (400 MHz, DMSO-d6) d 12.75 (br s, 1H), 7.24 (s,1H), and 1.48 (s, 9H) ppm. ¹³C NMR (400 MHz, CDCl₃) d 160.6, 152.7 (br),119.8, 110.6, 81.7, and 27.9 ppm. MS (ESI+) m/z (rel. intensity): 225.1(100, M⁸¹Br—(CH₃)₂C═CH₂ ⁺), 223.1 (100, M⁷⁹Br—(CH₃)₂C═CH₂ ⁺).

4.4 Alternate synthesis of tert-butyl(4-methylthio-1,3-thiazol-2-yl)carbamate (504)

tert-Butyl (4-bromo-1,3-thiazol-2-yl)carbamate (507, 3.9575 g, 14.177mmol), copper(I) iodide (2.7718 g, 14.554 mmol), and sodiummethylthiolate (5.0242 g, 71.682 mmol) were combined in a 100 mL flaskequipped with a stirbar and a water-jacketed condenser with a septum.The headspace was exchanged for dry nitrogen, and N,N-dimethylformamide(26 mL) was added. The reaction turned canary yellow, and then faded toa dull grey-pink suspension, and was stirred at room temperature for ca.1 min before lowering into a 136° C. oilbath set to 140° C., andstirred. Over the first 5-10 min of heating, the color faded to a lightyellow, and the reaction became homogenous. Out gassing/boiling wasobserved when stirring was stopped. The reaction was cooled to roomtemperature after 15 h at 140° C., and HPLC analysis showed completeconsumption of starting material. The reaction mixture was diluted withethyl acetate (ca. 200 mL) and filtered through a pad of celite, elutingwith ethyl acetate. The combined organics were washed with 1:1 1 MHCl/saturated NH₄Cl solution (250 mL), which resulted in a thickemulsion. The entire mixture was then filtered through amorphouscellulose, and the layers were separated. The organics were than washedwith 0.5 M HCl, and saturated NaHCO₃ solution. Another very fine powderdrops out of solution upon treatment with base. The suspension was againfiltered through celite, and the resulting solution was washed withbrine, dried with MgSO₄, filtered, and concentrated in vacuo to give agreen oil (3.17 g). The crude product was adsorbed onto ca. 15 g silicawith EtOAc, and dried in vacuo, and eluted through a pad of silica gel(ca. 80 g) with 500 mL hexanes (discarded) and 2 liters of 9:1hexanes/ethyl acetate, which was concentrated in vacuo to give 504 (2.41g, 69%) as an off-white solid.

Data for 504 is given above.

4.5 Synthesis of 4-(methylthio)-1,3-thiazol-2-amine (508)

tert-Butyl [4-(methylthio)-1,3-thiazol-2-yl]carbamate (504, 3.17 g, 12.9mmol) was dissolved in methylene chloride (130 mL), and trifluoroaceticacid (54 mL) was added to produce a bright yellow solution. The solutionwas lightly capped and stirred at room temperature for 8 hours, at whichpoint the reaction was complete. The solvents were removed in vacuo andthe resultant thick oil was suspended in 0.1 M HCl (50 mL), and thesolvent was removed. This was repeated once, and the resulting solidswere suspended in ethyl acetate (20 mL) and evaporated to give a finelydivided, free-flowing pink solid (2.0 g). The solids were re-suspendedin ethyl acetate (20 mL), sonicated, and filtered on a medium frit,washing with ethyl acetate (ca. 30 mL). The lavender solids werepartitioned solids between saturated NaHCO₃ solution (100 mL) anddichloromethane (100 mL). The layers were separated, and the aqueouslayer was extracted once with dichloromethane. The combined organicswere then washed with brine, dried with anhydrous MgSO₄, filtered, andconcentrated in vacuo to give 508 (1.33 g, 71%) as a dark oil, whichsolidified to a crystalline solid upon point cooling with dry ice, andletting stand.

Data for 508: ¹H-NMR (400 MHz, DMSO-d6) d 7.06 (br s, 2H), 6.11 (s, 1H),and 2.36 (s, 3H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) d 168.5, 144.7, 97.37,and 14.7 ppm; MS (ESI+) m/z (rel. intensity): 147.1 (100, M+H⁺), 132.0(20), and 105.0 (40).

4.6 Synthesis of 2-{[4-(methylthio)-1,3-thiazol-2-yl]carbamoyl}phenylacetate (509)

4-(Methylthio)-1,3-thiazol-2-amine (508, 672 mg, 4.60 mmol) wasdissolved in tetrahydrofuran (10.0 mL) to give a watermelon coloredsolution, and cooled to zero ° C. A solution of acetylsalicyloylchloride (0.9915 g) in tetrahydrofuran (1.4 mL) was added dropwise over1 minute, the bath was removed, and the reaction was stirred whileallowing the reaction to warm to room temperature over ca. 40 minutes.Triethylamine (0.670 mL, 4.81 mmol) was added dropwise over 3 minutes toproduce a dark suspension that was stirred for 15 hours. The solids wereremoved from the slurry by filtering on a medium frit, the solids werewashed with THF (ca. 20 mL), and the resulting solution wasconcentrated, dissolved in ethyl acetate, filtered through a plug ofmagnesol to remove polar colored impurities, and concentrated to give anorange crystalline solid (1.35 g). This crude material was adsorbed ontosilica gel with ethyl acetate, and purified by MPLC (eluting 1 litereach 6:1, 4:1, 3:1, and 2:1 Hex:EtOAc). Fractions were pooled andevaporated to give 509 (660.8 mg, 47%) as a near colorless solid.

Data for 509: ¹H-NMR (400 MHz, DMSO-d6) d 12.69 (br s, 1H), 7.77 (dd,J=7.8, 1.4 Hz, 1H), 7.62 (ddd, J=7.8, 7.8, 1.4 Hz, 1H), 7.40 (ddd,J=7.8, 7.8, 1.4 Hz, 1H), 7.27 (dd, J=8.0, 1.4 Hz, 1H), 6.87 (s, 1H),2.48 (s, 3H), and 2.22 (s, 3H) ppm; ¹³C-NMR (100 MHz, DMSO-d6) d 168.8,163.9, 158.3, 148.5, 145.2, 132.7, 129.5, 126.5, 125.8, 123.3, 105.4,20.7, and 15.0 ppm.; MS (ESI+) m/z (rel. intensity): 331.2 (20, M+Na⁺),309.3 (25, M+H⁺), 267.3 (70), 189.2 (30), 147.2 (100), 121.1 (40), 100.1(20), and 83.1 (65) m/z. MS (ESI−) m/z (rel. intensity): 265.3 (80,M−H⁻).

4.7 Synthesis of2-{[4-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenyl acetate (62)

2-{[4-(Methylthio)-1,3-thiazol-2-yl]carbamoyl}phenyl acetate (509, 201.1mg, 0.6521 mmol) was dissolved in methylene chloride (21 mL), andm-chloroperbenzoic acid (317.1 mg, 1.378 mmol) was added in a singleportion. The reaction was capped, and stirred at room temperature for100 minutes, when HPLC analysis of the mixture showed completeconversion to the desired sulfone. The reaction was quenched with 20%aq. Na₂S₂O₃ (20 mL), stirred 5 min, and the layers were separated. Theorganics were washed with saturate NaHCO₃ solution and brine, dried withanhydrous MgSO₄, filtered, and concentrated in vacuo to give a colorlesswhite solid (211.0 mg). The crude product was recrystallized fromrefluxing ethyl acetate/hexanes (5.0:2.0 mL), filtered, washed withhexanes, and dried in vacuo to give 62 (133.4 mg, 61%) a colorlesscrystalline solid.

Data for 62: ¹H-NMR (400 MHz, DMSO-d6) d 13.19 (br s, 1H), 8.11 (s, 1H),7.82 (d, J=7.8 Hz, 1H), 7.65 (dd, J=7.8, 7.8 Hz, 1H), 7.42 (dd, J=7.8,7.8 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 3.23 (s, 3H), and 2.23 (s, 3H) ppm;¹³C-NMR (100 MHz, DMSO-d6) d 168.8, 164.8, 160.1, 148.6, 148.3, 133.1,129.6, 126.0, 125.9, 123.4, 120.2, 42.0, and 20.7 ppm; MS (ESI+) m/z(rel. intensity): 341.1 (10, M+H⁺), 299.1 (20), 163.2 (15), 121.1 (100),100.1 (15), and 83.0 (50) m/z. MS (ESI−) m/z (rel. intensity): 339.2(10, M−H⁻) m/z.

4.8 Synthesis of2-hydroxy-N-[4-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide (60)

2-{[4-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenyl acetate (62,118.2 mg, 0.3473 mmol) was suspended in conc. hydrochloric acid (2.0 mL)and stirred rapidly. The slurry become homogenous momentarily, and thenre-precipitates. The suspension was stirred rapidly at 50° C. for 16hours before cooling, and filtering on a fine fritted funnel. The solidswere washed with water (ca. 5 mL), and dried in vacuo to give 60 as acolorless powder.

Data for 60: m.p.=231-235° C. (sealed tube); ¹H-NMR (400 MHz, DMSO-d6) d12.30 (br s, 1H), 11.64 (br s, 1H), 8.12 (s, 1H), 7.96 (dd, J=7.6, 1.6Hz, 1H), 7.65 (ddd, J=7.6, 7.6, 1.6 Hz, 1H), 7.07 (br d, J=7.6 Hz, 1H),7.01 (br dd, J=7.6, 7.6 Hz, 1H), and 3.25 (s, 3H) ppm; ¹³C-NMR (100 MHz,DMSO-d6) d 165.0, 159.4, 157.3, 148.3, 134.8, 130.3, 120.5, 119.8,117.2, 116.4, and 42.0 ppm. MS (ESI+) m/z (rel. intensity): 321.3 (30,M+Na⁺), 299.1 (10, M+H⁺), 242.1 (10), 201.1 (30), 179.1 (20), 121.1(100), 100.1 (20), and 56.0 (20) m/z. MS (ESI−) m/z (rel. intensity):297.2 (100, M−H⁻) m/z.

5.0 General procedures for the synthesis of4-hydroxy-N-[4-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide (84) and3-hydroxy-N-[4-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide (87)

The compounds 4-hydroxy-N-[4-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide(84) and 3-hydroxy-N-[4-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide(87), were prepared according to the following general synthetic scheme:

5.1 Synthesis of 4-(chlorocarbonyl)phenyl acetate (510)

Thionyl chloride (11.1 mL, 15.3 mmol) was added to 4-acetoxybenzoic acid(2.50 g, 13.9 mmol), and the reaction was warmed to reflux. The reactionwas cooled after heating for 3.5 hours, and concentrated in vacuo togive a colorless oil. Toluene was added to the residue and the mixturewas concentrated in vacuo to remove any residual thionyl chloride. Thisprocess was repeated twice more to give 510 (2.54 g, 92%) as a colorlessoil. This material was used in the next step without additionalpurification.

Data for 510: ¹H-NMR (400 MHz, CDCl₃) d 8.18 (d, J=8.9 Hz, 2H), 7.29 (d,J=8.9 Hz, 2H), 2.36 (s, 3H) ppm.

5.2 Synthesis of 3-(chlorocarbonyl)phenyl acetate (511)

Using the above procedure, reaction of with thionyl chloride (11.1 mL,15.3 mmol) and 3-acetoxybenzoic acid (2.50 g, 13.9 mmol) gave 511 (2.72g, 99%) as a colorless oil. This material was used in the next stepwithout additional purification.

Data for 511: ¹H-NMR (400 MHz, CDCl₃) δ 8.03 (ddd, J=8, 2, 1 Hz, 1H),7.87 (t, J=2 Hz, 1H), 7.52-7.60 (m, 1H), 7.46 (ddd, J=8, 2, 1 Hz, 1H),2.37 (s, 3H) ppm.

5.3 Synthesis of 4-{[4-(methylthio)-1,3-thiazol-2-yl]carbamoyl}phenylacetate (82)

Into a solution of 510 (0.815 g, 4.10 mmol) and dry THF (20.0 mL) wasadded a solution of triethylamine (0.572 mL, 4.10 mmol) and dry THF(5.00 mL), followed by a solution of 508 (0.500 g, 3.42 mmol) dissolvedin dry THF (15.0 mL). The reaction was stirred at room temperature.After stirring overnight, the reaction was concentrated in vacuo. Theresidue was partitioned between a saturated aqueous sodium bicarbonateand dichloromethane. The dichloromethane layer was washed a second timewith the saturated sodium bicarbonate solution and than twice with aq. 1M HCl. The dichloromethane layer was dried over anhydrous magnesiumsulfate and concentrated in vacuo to give crude 82 (1.15 g, >100%) as abrown solid. The crude product was suspended in diethyl ether, stirredand filtered. The filter pad was washed with ether several times, anddried in vacuo to give 82 (0.692 g, 63%) as a light brown solid.

Data for 82: mp=185.7-188.7° C.; ¹H-NMR (400 MHz, DMSO-d₆) δ 12.8 (s,1H), 8.14 (d, J=8.9 Hz, 2H), 7.32 (d, J=8.9 Hz, 2H), 6.89 (s, 1H), 2.50(s, 3H), 2.31 (s, 3H) ppm; MS (ESI+) m/z (rel. intensity): 100.1 (37),122.2 (98.3), 163.2 (49), 309.2 (100), 331.2 (29) m/z. MS (ESI−) m/z(rel. intensity): 111.0 (16), 203.2 (31), 307.2 (100).

5.4 Synthesis of 3-{[4-(methylthio)-1,3-thiazol-2-yl]carbamoyl}phenylacetate (85)

Into a solution of 511 (0.815 g, 4.10 mmol) and dry THF (25.0 mL) wasadded triethylamine (0.572 mL, 4.10 mmol), followed by a solution of the508 (0.500 g, 3.42 mmol) dissolved in dry THF (10.0 mL). The reactionwas stirred at room temperature. After stirring overnight, the reactionwas concentrated in vacuo. The residue was dissolved in ethyl acetateand washed once with water, three times with saturated aqueous. sodiumbicarbonate solution, and once with brine. The ethyl acetate solutionwas dried over anhydrous sodium sulfate and concentrated in vacuo togive crude 85 (1.28 g, >100%) as a red foam. The crude product wasdissolved in dichloromethane. Silica gel was added to thedichloromethane solution and the suspension was concentrated in vacuo.The residue was loaded on top of a 90 g silica gel cartridge and eluteddown the column using a solution of 20% ethyl acetate in hexane.Appropriate fractions of the major product were combined andconcentrated in vacuo to give 85 (0.614 g, 58%) as a tan solid. Thismaterial was used in the next step without further purification.

Data for 85: ¹H-NMR (400 MHz, DMSO-d₆) δ 12.8 (s, 1H), 8.01 (d, J=8 Hz,1H), 7.87 (t, J=2 Hz, 1H), 7.60 (t, J=8 Hz, 1H), 7.42 (ddd, J=8, 2, 1Hz, 1H), 6.90 (s, 1H), 2.50 (s, 3H), 2.32 (s, 3H) ppm.

5.5 Synthesis of4-{[4-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenyl acetate (83)

A solution of m-chloroperbenzoic acid (1.0 g, 6.0 mmol, maximum 77%)dissolved in dichloromethane (30 mL) was added to a suspension of 82(0.63 g, 2.0 mmol) in dichloromethane (60 mL). The reaction becamehomogeneous and the dark brown solution became lighter with time. After1.25 hours, saturated aqueous sodium thiosulfate was added to thereaction and the reaction mixture was stirred vigorously for 20 minutes.The yellow mixture was diluted with water and the resulting layersseparated. The organic layer was washed twice with saturated aqueoussodium bicarbonate, once with brine, dried with anhydrous sodium sulfateand concentrated in vacuo to give a beige solid. The crude product wasrecrystallized from 50% ethyl acetate/hexane (220 mL). After 4 days thesuspension was filtered, the filter pad was washed with hexanes and thendiethyl ether, and dried in vacuo at 55° C. overnight to give 83 (0.20g, 30%) as a light orange solid. Concentration of the filtrate in vacuofollowed by triturating the resulting residue with diethyl ether andfiltering off the resulting solid yielded an additional 45 mg of 83 as atan solid.

Data for 83: m.p.=242-246° C. (dec); ¹H-NMR (400 MHz, DMSO-d6) δ 13.2(s, 1H), 8.18 (d, J=8.7 Hz, 2H), 8.13 (s, 1H), 7.34 (d, J=8.7 Hz, 2H),3.25 (s, 3H), and 2.32 (s, 3H), ppm; MS (ESI+) m/z (rel. intensity):121.1 (40), 163.2 (50), 230.8 (10), 341.2 (100), 363.2 (70) m/z; MS(ESI−) m/z (rel. intensity): 339.3 (100).

5.6 Synthesis of3-{[4-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenyl acetate (86)

Using the above procedure for example 83, m-chloroperbenzoic acid (1.0g, 6.0 mmol, maximum 77%) dissolved in dichloromethane (30 mL) and 85(0.61 g, 2.0 mmol) dissolved in dichloromethane (30 mL) gave crude 86 asa white solid. The crude product was stirred in diethyl ether (30 mL)for 30 minutes, filtered and air dried to give 86 (0.59 g, 87%) as awhite solid.

Data for 86: m.p.=209-212° C.; ¹H-NMR (400 MHz, DMSO-d6) δ 13.2 (s, 1H),8.13 (s, 1H), 8.05 (d, J=8 Hz, 1H), 7.91 (t, J=2 Hz, 1H), 7.62 (t, J=8Hz, 1H), 7.45 (d, J=8 Hz, 1H), 3.26 (s, 3H), and 2.32 (s, 3H), ppm; MS(ESI+) m/z (rel. intensity): 121.1 (20), 163.2 (20), 299.2 (25), 341.2(100), 363.3 (40), 380.8 (10), 530.5 (10), 719.3 (5), 743.3 (5) m/z; MS(ESI−) m/z (rel. intensity): 339.3 (100).

5.7 Synthesis of4-hydroxy-N-[4-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide (84)

2 M hydrochloric acid (3.0 mL) was added to a suspension of 83 (0.12 g,0.35 mmol) in tetrahydrofuran (3.0 mL), and the resulting suspension waswarmed to reflux. The reaction became homogeneous upon heating. Afterrefluxing for 1.5 h, the reaction was allowed to cool to roomtemperature, and then partitioned between diethyl ether and water. Theether layer was washed with water, saturated aqueous sodium bicarbonate,and brine. The ether layer was dried with anhydrous sodium sulfate andconcentrated in vacuo. The residue triturated with ethyl acetate, thesolvent was removed under a stream of nitrogen, and the resulting solidwas dried in vacuo at 55° C. to give 84 (0.086 g, 82%) as a light yellowsolid.

Data for 84: mp=253-255° C. (dec). ¹H NMR (400 MHz, DMSO-d6) δ 12.9 (s,1H), 10.4 (s, 1H), 8.07 (s, 1H), 8.03 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.7Hz, 2H), and 3.24 (s, 3H) ppm. MS (ESI+) m/z (rel. intensity): 121.1(100), 299.3 (40), 321.2 (25), 355.3 (5) m/z. MS (ESI−) m/z (rel.intensity): 297.3 (100).

5.8 Synthesis of3-hydroxy-N-[4-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide (87)

Using the above procedure for example 84, compound 86 (0.36 g, 1.0 mmol)dissolved in tetrahydrofuran (10 mL) and 2 M hydrochloric acid (10 mL)gave 87 (0.29 g, 91%) as a white solid after the ether layer wasconcentrated in vacuo.

Data for 87: m.p.=258-259° C. (dec); ¹H-NMR (400 MHz, DMSO-d6) δ 13.1(s, 1H), 9.88 (s, 1H), 8.11 (s, 1H), 7.59 (d, J=8 Hz, 1H), 6.47 (s, 1H),7.35 (t, J=8 Hz, 1H), 7.05 (dd, J=8, 2 Hz, 1H), and 3.25 (s, 3H) ppm; MS(ESI+) m/z (rel. intensity): 218.3 (10), 299.3 (100), 321.2 (40) m/z; MS(ESI−) m/z (rel. intensity): 297.3 (100).

6.0 General procedures for the synthesis of4-hydroxy-N-[5-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide (80) and3-hydroxy-N-[5-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide (81)

The compounds 4-hydroxy-N-[5-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide(80) and 3-hydroxy-N[5-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide (81)were prepared according to the following general synthetic scheme:

6.1 Synthesis of 5-(methylthio)-1,3-thiazol-2-amine (512)

A solution of sodium thiomethoxide (1.09 g, 14.8 mmol) dissolved inmethanol (18.0 mL) was added to a suspension of 2-amino-5-bromothiazolemonohydrobromide 505 (2.50 g, 14.0 mmol) in anhydrous ethanol (18.0 mL)over 5 minutes. The reaction became homogeneous. A second solution ofsodium thiomethoxide (1.09 g, 14.8 mmol) dissolved in methanol (12.0 mL)was added to the reaction. The reaction was warmed to 45° C. for 40minutes then the heat was removed and the reaction was allowed to stirat room temperature overnight, when thin layer chromatography (1:1EtOAc/Hexane) indicated most of the starting material consumed alongwith the formation of a new product. Additional sodium thiomethoxide(0.20 g, 2.85 mmol) was added to the reaction and the reaction wasre-warmed to 50° C. After heating for 2 hours, the reaction was cooledto room temperature and concentrated in vacuo. The residue was dissolvedin dichloromethane and washed three times with water, once with brine,dried over anhydrous sodium sulfate and concentrated in vacuo to give512 (1.12 g, 55%) as an orange solid.

Data for 512: ¹H-NMR (400 MHz, DMSO-d₆) δ 7.20 (s, 2H), 6.97 (s, 1H),2.29 (s, 3H) ppm.

6.2 Synthesis of4-{[5-(methylsulfanyl)-1,3-thiazol-2-yl]carbamoyl}phenyl acetate (76)

Following the procedure for the synthesis of example 82, intermediate510 (0.815 g, 4.10 mmol) dissolved in dry THF (25.0 mL), triethylamine(0.572 mL, 4.10 mmol), and 512 (0.500 g, 3.42 mmol) dissolved in dry THF(10.0 mL) gave 76 (0.887 g, 84%) as a tan solid.

Data for 76: m.p.=193.3-195.5° C.; ¹H-NMR (400 MHz, DMSO-d₆) δ 12.8 (br.s., 1H), 8.13 (d, J=8.71 Hz, 2H), 7.58 (s, 1H), 7.32 (d, J=8.71 Hz, 2H),2.46 (s, 3H), 2.31 (s, 3H) ppm; MS (ESI+) m/z (rel. intensity): 121.0(100), 163.2 (48), 309.2 (34) m/z. MS (ESI−) m/z (rel. intensity): 292.2(100), 307.3 (48).

6.3 Synthesis of3-{[5-(methylsulfanyl)-1,3-thiazol-2-yl]carbamoyl}phenyl acetate (77)

Following the procedure for the synthesis of example 85, intermediate511 (0.815 g, 4.10 mmol) dissolved in dry THF (25.0 mL), triethylamine(0.572 mL, 4.10 mmol), and 512 (0.500 g, 3.42 mmol) dissolved in dry THF(10.0 mL) gave 77 (0.681 g, 65%) as a tan solid.

Data for 77: m.p.=135.2-136.2° C.; ¹H-NMR (400 MHz, DMSO-d₆) δ 12.8 (s,1H), 7.96-8.03 (m, 1H), 7.86 (t, J=2 Hz, 1H), 7.57-7.63 (m, 2H), 7.43(ddd, J=8, 2, 1 Hz, 1H), 2.47 (s, 3H), 2.32 (s, 3H) ppm; MS (ESI+) m/z(rel. intensity): 121.0 (40), 163.2 (100), 309.2 (85), 331.2 (11) m/z;MS (ESI−) m/z (rel. intensity): 292.3 (100), 307.3 (49).

6.4 Synthesis of4-{[5-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenyl acetate (78)

A solution of m-chloroperbenzoic acid (0.611 g, 2.73 mmol, maximum 77%)dissolved in dichloromethane (10.0 mL) was added drop wise over 15minutes to a solution of 76 (0.841 g, 2.73 mmol) dissolved indichloromethane (35.0 mL), and the reaction was stirred at roomtemperature for 1.25 hours. A second solution of m-chloroperbenzoic acid(0.611 g, 2.73 mmol) dissolved in dichloromethane (10.0 mL) was added tothe reaction over 15 minutes, and the resulting solution was stirred foran additional 2.5 hours at room temperature. The reaction waspartitioned between dichloromethane and saturated aq. sodiumthiosulfate. The organic layer was washed with saturated aq. sodiumthiosulfate, twice with saturated aq. sodium bicarbonate, and once withbrine. The dichloromethane layer was concentrated in vacuo (withoutdrying) to give crude 78 (0.80 g, 86%). The crude product was stirredwith chloroform (250 mL) and the suspension filtered. The pad was washedonce with chloroform and air dried to give 78 (0.559 g, 60%) as a whitesolid.

Data for 78: m.p.=279.6-280.6° C.; ¹H-NMR (400 MHz, DMSO-d₆) δ 13.3 (br.s., 1H), 8.20 (s, 1H), 8.18 (d, J=8.71 Hz, 2H), 7.35 (d, J=8.71 Hz, 2H),3.39 (s, 3H), 2.32 (s, 3H) ppm; MS (ESI+) m/z (rel. intensity): 121.0(100), 163.2 (72), 341.2 (63), 363.2 (59) m/z; MS (ESI−) m/z (rel.intensity): 259.3 (17), 339.3 (100).

6.5 Synthesis of3-{[5-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenyl acetate (79)

A solution of m-chloroperbenzoic acid (0.458 g, 2.04 mmol, maximum 77%)dissolved in dichloromethane (8.0 mL) was added drop wise over 15minutes to a solution of 77 (0.630 g, 2.04 mmol) dissolved indichloromethane (25.0 mL). The reaction was stirred at room temperaturefor 1.25 hours. A second solution of m-chloroperbenzoic acid (0.458 g,2.04 mmol) dissolved in dichloromethane (8.0 mL) was then added to thereaction over 10 minutes, and stirred for an additional 4.5 hours atroom temperature. The reaction was then partitioned betweendichloromethane and saturated aqueous sodium thiosulfate. The organiclayer was washed again with a saturated aqueous sodium thiosulfate,twice with saturated aqueous sodium bicarbonate and once with brine. Thedichloromethane layer was dried over magnesium sulfate and concentratedin vacuo to give crude 79 (0.704 g, >100%), which was contaminated withtraces of residual 3-chlorobenzoic acid. The crude product wasre-dissolved in ethyl acetate and washed three times with a saturatedaq. sodium bicarbonate, dried using magnesium sulfate and concentratedin vacuo to give a tan solid. The residue was dissolved in THF, and thelight brown solution was filtered through a plug of Magnesol. the filterpad was washed well with THF, and the colorless filtrate wasconcentrated in vacuo to give 79 (0.530 g, 76%) as a white solid.

Data for 79: m.p.=186.5° C. (dec); ¹H-NMR (400 MHz, DMSO-d₆) δ 13.4 (s,1H), 8.20 (s, 1H), 8.04 (d, J=8 Hz, 1H), 7.91 (t, J=2 Hz, 1H), 7.63 (t,J=8 Hz, 1H), 7.47 (ddd, J=8, 2, 1 Hz, 1H), 3.40 (s, 3H), 2.32 (s, 3H)ppm; MS (ESI+) m/z (rel. intensity): 121.0 (31), 163.2 (100), 341.2(75), 363.2 (24) m/z; MS (ESI−) m/z (rel. intensity): 259.2 (22), 339.2(100).

6.6 Synthesis of4-hydroxy-N-[5-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide (80)

2 M hydrochloric acid (45.0 mL) was added to a suspension of 78 (0.439g, 1.29 mmol) in tetrahydrofuran (20.0 mL), and the suspension waswarmed to reflux. The reaction became homogeneous upon heating. Afterrefluxing for 4 hours, the reaction was allowed to cool to roomtemperature, and stood at room temperature overnight before the reactionwas filtered. The filter pad was washed with water then dried in vacuoat 70° C. to give 80 (0.2489 g, 64.6%) as a white crystalline solid.

Data for 80: m.p.=ca. 242° C. (dec). The decomposed solids then melt at252.5-255.5° C.; ¹H-NMR (400 MHz, DMSO-d₆) δ 13.1 (br. s., 1H), 10.5 (s,1H), 8.22 (s, 1H), 8.09 (d, J=8.71 Hz, 2H), 6.96 (d, J=8.71 Hz, 2H),3.43 (s, 3H) ppm; MS (ESI+) m/z (rel. intensity): 121.1 (100), 299.2(10), 321.1 (4) m/z; MS (ESI−) m/z (rel. intensity): 177.2 (16), 217.2(24), 297.2 (100).

6.7 Synthesis of3-hydroxy-N-[5-(methylsulfonyl)-1,3-thiazol-2-yl]benzamide (81)

2 M hydrochloric acid (40.0 mL) was added to a suspension of 79 (0.370g, 1.09 mmol) in tetrahydrofuran (17.0 mL), and the reaction was warmedto reflux. The reaction became homogeneous upon heating. After refluxingfor 4 hours, the reaction was allowed to cool to room temperature, andconcentrated in vacuo. The residue was suspended in water and filtered.The filter pad was washed with water, air dried, and then re-dissolvedin a minimum amount of warm THF. Water was added to the warm THFsolution until the solution turned turbid, and the resulting mixture wasallowed to cool to room temperature. Additional water was added, and awhite solid formed on standing. The crystalline product was filtered,and the filter pad was washed with water, and dried in vacuo at 70° C.to give 81 (0.182 g, 56%) as a white crystalline solid.

Data for 81: m.p.=271.1-272.3° C.; ¹H-NMR (400 MHz, DMSO-d₆) δ 13.2 (s,1H), 9.91 (s, 1H), 8.19 (s, 1H), 7.58 (d, J=8 Hz, 1H), 7.46 (t, J=2 Hz,1H), 7.37 (t, J=8 Hz, 1H), 7.06 (dd, J=8, 2 Hz, 1H), 3.39 (s, 3H) ppm;MS (ESI+) m/z (rel. intensity): 100.1 (42) 121.1 (100), 299.2 (44),321.1 (8) m/z; MS (ESI−) m/z (rel. intensity): 217.2 (29), 297.2 (100).

7.0 Synthesis of 2-hydroxy-N-(5-(methylsulfonyl)thiazol-2-yl)benzamide(6)

The compound, 2-hydroxy-N-(5-(methylsulfonyl)thiazol-2-yl)benzamide (6),was prepared according to the following synthetic scheme:

7.1 Alternate synthesis of 5-(methylthio)thiazol-2-amine (512) 7.1Alternate synthesis of 5-(methylthio)thiazol-2-amine (512)

A solution of bromine (1.9 mL, 37.1 mmol, 1.01 eq.) and dioxane (0.1cm³, 0.3 eq.) in DCM (20 mL) was added dropwise to a stirred solution of(methylthio)acetaldehyde dimethyl acetal (5.00 g, 36.7 mmol, 1.0 eq.) inDCM (80 mL) at 0° C. over three hours. This mixture was allowed to warmto room temperature and stirred at this temperature for 30 minutes untilNMR analysis revealed the disappearance of starting material. DCM wasremoved under vacuo. Crude bromide 513 was dissolved in THF (50 mL),which was followed by the addition of solution of thiourea (5.58 g, 2.0eq) in THF (100 mL) and water (20 mL). The solution was refluxedovernight. Solvent was removed under vacuo and the crude product wasextracted with EtOAc (50 mL) three times. The combined organic layerswere washed with brine solution and dried over anhydrous MgSO₄. Productpurification through flash column chromatography gave the requiredproduct, 2-amino-5-methylthiothiazole 512 (1.35 g, 25.2% yield), as abrown solid.

Data for 512: TLC (silica gel) R_(f)=0.2 (1:1, Hex:EtOAc); ¹H-NMR(CDCl₃, 200 MHz), 2.35 (3H, s, CH₃), 5.46 (2H, s, NH₂), 7.06 (1H, s,CH); ¹H (DMSO-d, 400 MHz), 2.29 (3H, s, CH₃), 6.96 (1H, s, CH), 7.16(2H, s, NH₂); ¹³C-NMR (100 MHz, DMSO-d), 22.6, 115.8, 144.9, 171.8; m/z(CI+H)⁺ 147; HRMS. found, m/z 147.00540, C₄H₇N₂S₂ (MH⁺) requires m/z,147.00507 (+2.4 ppm).

7.2 Synthesis of 2-(5-(methylthio)thiazol-2-ylcarbamoyl)phenyl acetate(69)

Under nitrogen a solution of acetylsalicyloyl chloride (1.237 g, 6.20mmol, 1.3 eq) in THF (40 mL) was added to a stirred solution of5-(methylthio)thiazol-2-amine ? (700.0 mg, 4.79 mmol, 1.0 eq) in dry THF(mL). This was followed by the addition of triethylamine (0.67 mL, 4.79mmol, 1.0 eq). The reaction mixture was stirred at room temperature andmonitored by TLC. After two hours, reaction was filtered throughsintered funnel and solvent removed in vacuo. The crude product wasdissolved in EtOAc (150 mL) and washed twice each with 1M HCl andsaturated aq. sodium hydrogen carbonate solutions. The organic fractionwas dried over MgSO₄ followed the removal of solvent. Flash columnchromatography yielded the pure product 69 (1.450 g, 98%) as a solid.

Data for 69: m.p.=145-147° C.; TLC (silica gel) R_(f)=0.36 (Hex:EtOAc,1:1); ¹H-NMR (DMSO-d, 400 MHz), 2.23 (3H, s, CH₃), 2.47 (3H, s, CH₃),7.28 (1H, dd, J=1.0, 8.0 Hz, ArH), 7.41 (1H, td, J=1.0, 7.6 Hz, ArH),7.56 (1H, s, CH), 7.63 (1H, td, J=1.7, 8.0 Hz, ArH), 7.78 (1H, dd,J=1.7, 7.6 Hz, ArH), 12.70 (1H, s, NH); ¹³C-NMR (DMSO-d, 100 MHz), 21.1,22.0, 123.7, 124.6, 126.2, 126.9, 130.0, 133.1, 141.6, 148.9, 160.0,164.5, 169.2; m/z (CI) 309 (MH⁺); HRMS. found 309.03654, C₁₃H₁₃N₂O₃S₂requires 309.03677, (−0.8 ppm).

7.3 Synthesis of 2-(5-(methylsulfonyl)thiazol-2-ylcarbamoyl)phenylacetate (7)

A solution of mCPBA (70-75%, 1.04 g, 4.2 mmol, 1.2 eq) in DCM (20 mL)was added dropwise to a stirred solution of 69 (1.1 g, 3.57 mmol, 1.0eq) in DCM (50 mL) over a period of 30 minutes. Reaction was stirred forfurther 30 minutes at room temperature. A second portion of mCPBA(70-75%, 1.04 g, ˜4.2 mmol, 1.18 eq) in DCM (20 mL) was added dropwiseover 30 minutes. The reaction was stirred for 1 hour. The reaction wasquenched with saturated aq. sodium thiosulfate solution and the organiclayer was extracted two times each with aq. saturated sodium hydrogencarbonate solution and 1M HCl, respectively. The combined organic layerswere washed with brine solution and dried over anhydrous MgSO₄. Solventremoval in vacuo and flash column chromatography (1:1 EtOAc, Hex→EtOAc)afforded 7 (1.15 g, 95%) as a white solid.

Data for 7: m.p.=173-175° C.; TLC (silica gel) R_(f)=0.27 (EtOAc);¹{tilde over (H)}-NMR (400 MHz, DMSO-d), 2.25 (3H, s, CH₃), 3.38 (3H, s,CH₃), 7.31 (1H, dd, J=1.0, 8.0 Hz, ArH), 7.44 (1H, td, J=1.0, 7.6 Hz,ArH), 7.67 (1H, td, J=1.6, 7.6 Hz, ArH), 7.83 (1H, dd, J=1.6, 8.0 Hz,ArH), 8.17 (1H, s, CH); ¹³C-NMR (100 MHz, DMSO-d), 21.1, 46.2, 123.8,122.2, 126.3, 130.1, 130.7, 133.6, 144.6, 149.0, 163.3, 165.3, 169.2; MSm/z (CI+H)⁺ 341, (100%), 299 (36%), 221 (83%).

7.3 Synthesis of 2-hydroxy-N-(5-(methylsulfonyl)thiazol-2-yl)benzamide(6)

A solution of 7 (1.0 g, 2.94 mmol, 1.0 eq) dissolved in THF (20 mL) wasadded under stirring to 2M HCl (100 mL). The reaction was refluxed forone hour and allowed to cool under stirring over one hour. The productwas filtered using a sintered glass funnel, washed with distilled waterand THF and dried in high vacuum to afford 834 mg (95%) of 6 as acolorless solid.

Data for 6: m.p.=282-283° C.; ¹H-NMR (DMSO-d, 400 MHz), 3.39 (3H, s,CH₃SO₂), 7.01 (1H, t, J=7.5 Hz, ArH), 7.10 (1H, d, J=7.5 Hz, ArH), 7.52(1H, t, J=7.5 Hz, ArH), 7.96 (1H, d, J=7.5 Hz, ArH) and 8.17 (1H, s,4′-H); ¹³C-NMR (100 MHz, DMSO-d) 46.2, 117.0, 117.6, 120.1, 130.5,130.8, 135.2, 144.2, 157.7, 163.1 and 165.6; MS (CI) m/z 299 (MH⁺) and316 (MNH₄ ⁺); HRMS. found, m/z 299.01696, C₁₁H₁₁N₂O₄S₂ (MH⁺) requiresm/z, 299.01602.

Although the foregoing refers to particular preferred embodiments, itwill be understood that the present invention is not so limited. It willoccur to those of ordinary skill in the art that various modificationsmay be made to the disclosed embodiments and that such modifications areintended to be within the scope of the present invention.

All of the publications, patent applications and patents cited in thisspecification are incorporated herein by reference in their entirety.

What is claimed is:
 1. A compound having a formula (I)

wherein one of R₆ or R₉ is C₁-C₆ alkylsulfonyl, and the other ishydrogen, or a pharmaceutically acceptable salt or ester thereof.
 2. Acompound according to claim 1, selected from the group consisting ofstructures:


3. A compound according to claim 1, selected from the group consistingof:


4. The compound of claim 1, wherein R₆ or R₉ is SO₂CH₃ and the other R₆or R₉ is H.
 5. The compound of claim 1, wherein the compound of formula(I) is the pharmaceutically acceptable ester.
 6. The compound of claim5, wherein the pharmaceutically acceptable ester is a (C₁-C₆)-acyloxy.7. The compound of claim 1, wherein the compound is the pharmaceuticallyacceptable salt.
 8. The compound of claim 7, wherein thepharmaceutically acceptable salt is selected from the group consistingof acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptanoate, glycero-phosphate, hemisulfate, heptanoate,hexanoate, hydrochloride hydrobromide, hydroiodide,2-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate andundecanoate.
 9. The compound of claim 4, wherein the compound of formula(I) is the pharmaceutically acceptable ester.
 10. The compound of claim9, wherein the pharmaceutically acceptable ester is a (C₁-C₆)-acyloxy.11. A pharmaceutical composition comprising a compound of claim 1 and acarrier.
 12. A pharmaceutical composition comprising a compound of claim2 and a carrier.
 13. A pharmaceutical composition comprising a compoundof claim 3 and a carrier.
 14. A pharmaceutical composition comprising acompound of claim 4 and a carrier.
 15. A pharmaceutical compositioncomprising a compound of claim 5 and a carrier.
 16. A pharmaceuticalcomposition comprising a compound of claim 6 and a carrier.
 17. Apharmaceutical composition comprising a compound of claim 7 and acarrier.
 18. A pharmaceutical composition comprising a compound of claim8 and a carrier.
 19. A pharmaceutical composition comprising a compoundof claim 9 and a carrier.
 20. A pharmaceutical composition comprising acompound of claim 10 and a carrier.